{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:09:47Z","timestamp":1788916187407,"version":"build-2803163510"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:p>\n                    Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS\u2010related cholestasis. Two hundred and ninety\u2010three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed\n                    <jats:italic toggle=\"yes\">JAGGED1<\/jats:italic>\n                    mutations in 91% and\n                    <jats:italic toggle=\"yes\">NOTCH2<\/jats:italic>\n                    mutations in 4%. Growth was impaired with mean height and weight\n                    <jats:italic toggle=\"yes\">z<\/jats:italic>\n                    \u2010scores of &lt;\u22121.0 at all ages. Regression analysis revealed that every 10\u00a0mg\/dL increase in total bilirubin was associated with a decrease in height\n                    <jats:italic toggle=\"yes\">z<\/jats:italic>\n                    \u2010score by 0.10 (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.03) and weight\n                    <jats:italic toggle=\"yes\">z<\/jats:italic>\n                    \u2010score by 0.15 (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.007). Total bilirubin was higher for younger participants (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.03) with a median of 6.9 mg\/dL for those less than 1 year old compared with a median of 1.3 mg\/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within\u2010individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant\u2013free survival at the age of 18.5 years was 24%.\n                    <jats:italic toggle=\"yes\">Conclusions<\/jats:italic>\n                    : This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.\n                  <\/jats:p>","DOI":"10.1002\/hep4.1468","type":"journal-article","created":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T11:22:52Z","timestamp":1579692172000},"page":"387-398","source":"Crossref","is-referenced-by-count":80,"title":["Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study"],"prefix":"10.1097","volume":"4","author":[{"given":"Binita M.","family":"Kamath","sequence":"first","affiliation":[{"name":"The Hospital for Sick Children,University of Toronto,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Surgery,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P.","family":"Goodrich","sequence":"additional","affiliation":[{"name":"Department of Surgery,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Loomes","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene","family":"Romero","sequence":"additional","affiliation":[{"name":"Children\u2019s Healthcare of Atlanta,Emory University School of Medicine,Atlanta,GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Heubi","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Leung","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine,Texas Children\u2019s Hospital,Houston,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy B.","family":"Spinner","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Piccoli","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estella M.","family":"Alonso","sequence":"additional","affiliation":[{"name":"Ann and Robert H. Lurie Children\u2019s Hospital,Northwestern University,Chicago,IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Guthery","sequence":"additional","affiliation":[{"name":"Primary Children\u2019s Hospital,University of Utah,Salt Lake City,UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saul J.","family":"Karpen","sequence":"additional","affiliation":[{"name":"Children\u2019s Healthcare of Atlanta,Emory University School of Medicine,Atlanta,GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara L.","family":"Mack","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine,Children\u2019s Hospital Colorado,Aurora,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean P.","family":"Molleston","sequence":"additional","affiliation":[{"name":"Riley Hospital for Children,Indiana University,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen F.","family":"Murray","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Hospital,University of Washington School of Medicine,Seattle,WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,University of California, San Francisco,San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Squires","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,UPMC Children\u2019s Hospital of Pittsburgh,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Teckman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,Saint Louis University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasper S.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery,Children\u2019s Hospital Los Angeles,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Thompson","sequence":"additional","affiliation":[{"name":"Institute of Liver Studies,King\u2019s College London,London,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Magee","sequence":"additional","affiliation":[{"name":"Department of Surgery,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J.","family":"Sokol","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine,Children\u2019s Hospital Colorado,Aurora,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Childhood Liver Disease Research Network (ChiLDReN)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"key":"hep41468-bib-0001-20240114","first-page":"325","article-title":"Alagille syndrome today","volume":"19","year":"1996","journal-title":"Clin Invest Med"},{"key":"hep41468-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1136\/jmg.34.2.152","article-title":"Alagille syndrome","volume":"34","year":"1997","journal-title":"J Med Genet"},{"key":"hep41468-bib-0003-20240114","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1136\/jmg.40.12.891","article-title":"Consequences of JAG1 mutations","volume":"40","year":"2003","journal-title":"J Med Genet"},{"key":"hep41468-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1097\/00005176-199910000-00011","article-title":"Variable morbidity in alagille syndrome: a review of 43 cases","volume":"29","year":"1999","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"hep41468-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/ng0797-243","article-title":"Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1","volume":"16","year":"1997","journal-title":"Nat Genet"},{"key":"hep41468-bib-0006-20240114","first-page":"435","article-title":"Clinical utility gene card for: Alagille syndrome (ALGS)","volume":"22","year":"2014","journal-title":"Eur J Hum Genet"},{"key":"hep41468-bib-0007-20240114","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/humu.21231","article-title":"Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis","volume":"31","year":"2010","journal-title":"Hum Mutat"},{"key":"hep41468-bib-0008-20240114","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1136\/jmedgenet-2011-100544","article-title":"NOTCH2 mutations in Alagille syndrome","volume":"49","year":"2012","journal-title":"J Med Genet"},{"key":"hep41468-bib-0009-20240114","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cld.2005.10.008","article-title":"Whatever happened to \u201cneonatal hepatitis\u201d?","volume":"10","year":"2006","journal-title":"Clin Liver Dis"},{"key":"hep41468-bib-0010-20240114","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/hep.510290331","article-title":"Features of Alagille syndrome in 92 patients: frequency and relation to prognosis","volume":"29","year":"1999","journal-title":"Hepatology"},{"key":"hep41468-bib-0011-20240114","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1136\/gut.49.3.431","article-title":"Outcome of liver disease in children with Alagille syndrome: a study of 163 patients","volume":"49","year":"2001","journal-title":"Gut"},{"key":"hep41468-bib-0012-20240114","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1097\/MPG.0000000000002333","article-title":"Clinically evident portal hypertension","volume":"68","year":"2019","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"hep41468-bib-0013-20240114","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/0016-5085(88)90301-0","article-title":"Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis","volume":"95","year":"1988","journal-title":"Gastroenterology"},{"key":"hep41468-bib-0014-20240114","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1080\/01621459.1991.10475011","article-title":"Nonparametric estimation from cross\u2010sectional survival data","volume":"86","year":"1991","journal-title":"J Am Stat Assoc"},{"key":"hep41468-bib-0015-20240114","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/biomet\/93.2.367","article-title":"Nonparametric estimation with left\u2010truncated semicompeting risks data","volume":"93","year":"2006","journal-title":"Biometrika"},{"key":"hep41468-bib-0016-20240114","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/MPG.0b013e3181f1572d","article-title":"Diagnosis of Alagille syndrome\u201025 years of experience at King's College Hospital","volume":"52","year":"2011","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"hep41468-bib-0017-20240114","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/1098-1004(2001)17:1<18::AID-HUMU3>3.0.CO;2-T","article-title":"Jagged1 mutations in alagille syndrome","volume":"17","year":"2001","journal-title":"Hum Mutat"},{"key":"hep41468-bib-0018-20240114","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/1098-1004(200102)17:2<151::AID-HUMU8>3.0.CO;2-T","article-title":"Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients","volume":"17","year":"2001","journal-title":"Hum Mutat"},{"key":"hep41468-bib-0019-20240114","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0022-3476(95)70298-9","article-title":"Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy","volume":"127","year":"1995","journal-title":"J Pediatr"},{"key":"hep41468-bib-0020-20240114","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/S1089-3261(05)70140-9","article-title":"Alagille syndrome: the widening spectrum of arteriohepatic dysplasia","volume":"4","year":"2000","journal-title":"Clin Liver Dis"},{"key":"hep41468-bib-0021-20240114","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1053\/jlts.2000.9739","article-title":"Does liver transplantation affect growth pattern in Alagille syndrome?","volume":"6","year":"2000","journal-title":"Liver Transpl"},{"key":"hep41468-bib-0022-20240114","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0022-3476(99)70411-7","article-title":"Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome","volume":"134","year":"1999","journal-title":"J Pediatr"},{"key":"hep41468-bib-0023-20240114","first-page":"1477","article-title":"Growth hormone insensitivity associated with elevated circulating growth hormone\u2010binding protein in children with Alagille syndrome and short stature","volume":"76","year":"1993","journal-title":"J Clin Endocrinol Metab"},{"key":"hep41468-bib-0024-20240114","first-page":"495","article-title":"Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea","volume":"35","year":"2002","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"hep41468-bib-0025-20240114","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1002\/lt.23437","article-title":"Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience","volume":"18","year":"2012","journal-title":"Liver Transpl"},{"key":"hep41468-bib-0026-20240114","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1097\/MPG.0b013e3181cb9629","article-title":"Pathologic lower extremity fractures in children with Alagille syndrome","volume":"51","year":"2010","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"hep41468-bib-0027-20240114","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/hep.30196","article-title":"Bone density in children with chronic liver disease correlates with growth and cholestasis","volume":"69","year":"2019","journal-title":"Hepatology"},{"key":"hep41468-bib-0028-20240114","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1038\/s41598-017-02574-7","article-title":"Requirement for Jagged1\u2010Notch2 signaling in patterning the bones of the mouse and human middle ear","volume":"7","year":"2017","journal-title":"Sci Rep"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep4.1468","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep4.1468","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep4.1468","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep4.1468","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,14]],"date-time":"2024-01-14T12:06:02Z","timestamp":1705233962000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep4.1468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,22]]},"references-count":28,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020]]}},"URL":"https:\/\/doi.org\/10.1002\/hep4.1468","relation":{},"ISSN":["2471-254X","2471-254X"],"issn-type":[{"value":"2471-254X","type":"print"},{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,22]]}}}