{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T13:11:00Z","timestamp":1769346660595,"version":"3.49.0"},"reference-count":27,"publisher":"The Endocrine Society","issue":"3","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by congenital heart disease, hepatic cholestasis, dyslipidemia, and characteristic facies since infancy. Cholestatic hypercholesterolemia in patients diagnosed with AGS is occasionally refractory and resistant to conventional treatments. We report the case of a 4-month-old boy diagnosed with AGS and refractory dyslipidemia due to cholestatic liver disease. He had repeated episodes of cyanosis due to pulmonary artery atresia since birth and underwent a Blalock-Taussig shunt procedure at age 3 months. At age 4 months, cholestatic hyperbilirubinemia deteriorated to a serum total bilirubin level of 19.9 mg\/dL. At age 12 months, a laboratory test revealed severe dyslipidemia (serum total cholesterol, 1796 mg\/dL; serum triglycerides [TGs], 635 mg\/dL), and the presence of xanthomas. A pathogenic variant of the JAG1 gene (c.1326G\u2005&amp;gt;\u2005A, p.Trp442X) was detected through genetic testing. Oral ursodeoxycholate normalized hyperbilirubinemia with a subtle improvement in dyslipidemia. Combination therapy with pravastatin and fenofibrate did not successfully improve dyslipidemia. At age 20 months, altering pravastatin to atorvastatin was effective in normalizing serum cholesterol and TGs with no adverse events.<\/jats:p>\n               <jats:p>Combination therapy with atorvastatin and fenofibrate was successful in improving refractory dyslipidemia in a child with AGS. Atorvastatin is a well-known strong statin that can lower serum cholesterol, and fenofibrate can lower serum TG levels. We propose that atorvastatin be taken into consideration for the treatment of persistent hyperlipidemia in patients diagnosed with AGS, because atorvastatin upregulates bile acid synthesis and lipoprotein scavenging, and inhibits intrinsic cholesterol production.<\/jats:p>","DOI":"10.1210\/jendso\/bvac005","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T21:58:11Z","timestamp":1642543091000},"source":"Crossref","is-referenced-by-count":6,"title":["A Case of Infantile Alagille Syndrome With Severe Dyslipidemia: New Insight into Lipid Metabolism and Therapeutics"],"prefix":"10.1210","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3678-9918","authenticated-orcid":false,"given":"Hisakazu","family":"Nakajima","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan"},{"name":"Department of Pediatrics, Midorigaoaka Hospital, Takatsuki, Osaka, 569-1121, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Tsuma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7544-0399","authenticated-orcid":false,"given":"Shota","family":"Fukuhara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuki","family":"Kodo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"issue":"1","key":"2022020904394333200_CIT0001","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0022-3476(75)80706-2","article-title":"Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur","volume":"86","author":"Alagille","year":"1975","journal-title":"J Pediatr."},{"issue":"2","key":"2022020904394333200_CIT0002","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0022-3476(87)80153-1","article-title":"Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases","volume":"110","author":"Alagille","year":"1987","journal-title":"J Pediatr."},{"issue":"2","key":"2022020904394333200_CIT0003","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/MPG.0b013e318297e384","article-title":"Management of cholestatic pruritus in paediatric patients with Alagille syndrome: the King\u2019s College Hospital experience","volume":"57","author":"Kronsten","year":"2013","journal-title":"J Pediatr Gastroenterol Nutr."},{"issue":"1","key":"2022020904394333200_CIT0004","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1097\/00005176-200301000-00011","article-title":"Lack of cholesterol-lowering effect of graded doses of cholestyramine in children with Alagille syndrome: a pilot study","volume":"36","author":"Larrosa-Haro","year":"2003","journal-title":"J Pediatr Gastroenterol Nutr."},{"issue":"12","key":"2022020904394333200_CIT0005","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1002\/humu.23879","article-title":"Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification","volume":"40","author":"Gilbert","year":"2019","journal-title":"Hum Mutat."},{"issue":"4","key":"2022020904394333200_CIT0006","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/0003319720975635","article-title":"The effect of long-term atorvastatin therapy on carotid intima-media thickness of children with dyslipidemia","volume":"72","author":"Karapostolakis","year":"2021","journal-title":"Angiology."},{"issue":"2","key":"2022020904394333200_CIT0007","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/pedi.12245","article-title":"A randomized, double blind, placebo-controlled pilot trial of the safety and efficacy of atorvastatin in children with elevated low-density lipoprotein cholesterol (LDL-C) and type 1 diabetes","volume":"16","author":"Canas","year":"2015","journal-title":"Pediatr Diabetes."},{"issue":"5","key":"2022020904394333200_CIT0008","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.jacl.2016.05.010","article-title":"A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia","volume":"10","author":"Langslet","year":"2016","journal-title":"J Clin Lipidol."},{"key":"2022020904394333200_CIT0009","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.jpeds.2016.01.006","article-title":"Molecular genetic dissection and neonatal\/infantile intrahepatic cholestasis using targeted next-generation sequencing","volume":"171","author":"Togawa","year":"2016","journal-title":"J Pediatr."},{"issue":"3","key":"2022020904394333200_CIT0010","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/sj.ejhg.5200613","article-title":"Parental mosaicism of JAG1 mutations in families with Alagille syndrome","volume":"9","author":"Giannakudis","year":"2001","journal-title":"Eur J Hum Genet."},{"issue":"11","key":"2022020904394333200_CIT0011","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1111\/apa.13981","article-title":"Combined genetic analyses achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome","volume":"106","author":"Ohashi","year":"2017","journal-title":"Acta Paediatr."},{"issue":"4","key":"2022020904394333200_CIT0012","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/S0016-5085(96)70071-9","article-title":"Abnormal lipoprotein pattern in patients with Alagille syndrome depends on icterus severity","volume":"111","author":"Davit-Spraul","year":"1996","journal-title":"Gastroenterology."},{"key":"2022020904394333200_CIT0013","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cca.2014.10.034","article-title":"Negative feedback loop of cholesterol regulation is impaired in the livers of patients with Alagille syndrome","volume":"440","author":"Miyahara","year":"2015","journal-title":"Clin Chim Acta."},{"issue":"9","key":"2022020904394333200_CIT0014","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1194\/jlr.R200008-JLR200","article-title":"Hepatic lipase: a pro- or anti-atherogenic protein?","volume":"43","author":"Jansen","year":"2002","journal-title":"J Lipid Res."},{"issue":"9","key":"2022020904394333200_CIT0015","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1194\/jlr.M400133-JLR200","article-title":"SR-BI- and ABCA1-mediated cholesterol efflux to serum from patients with Alagille syndrome","volume":"45","author":"Yancey","year":"2004","journal-title":"J Lipid Res."},{"issue":"2","key":"2022020904394333200_CIT0016","first-page":"350","article-title":"New JAG1 mutation causing Alagille syndrome presenting with severe hypercholesterolemia: case report with emphasis on genetics and lipid abnormalities","volume":"102","author":"Hannoush","year":"2017","journal-title":"J Clin Endocrinol Metab."},{"issue":"12","key":"2022020904394333200_CIT0017","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1194\/jlr.M053124","article-title":"Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice","volume":"55","author":"Fu","year":"2014","journal-title":"J Lipid Res."},{"issue":"8","key":"2022020904394333200_CIT0018","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1194\/jlr.M067488","article-title":"Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice","volume":"57","author":"Schonewille","year":"2016","journal-title":"J Lipid Res."},{"issue":"3","key":"2022020904394333200_CIT0019","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1111\/j.1476-5381.2009.00350.x","article-title":"Atorvastatin and fenofibrate increase apolipoprotein AV and decrease triglycerides by up-regulating peroxisome proliferator-activated receptor-alpha","volume":"158","author":"Huang","year":"2009","journal-title":"Br J Pharmacol"},{"issue":"1","key":"2022020904394333200_CIT0020","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11883-020-0823-5","article-title":"Pemafibrate, a new selective PPAR\u03b1 modulator: concept and its clinical applications for dyslipidemia and metabolic diseases","volume":"22","author":"Yamashita","year":"2020","journal-title":"Curr Atheroscler Rep."},{"issue":"4","key":"2022020904394333200_CIT0021","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1172\/JCI88894","article-title":"Distinct but complementary contributions of PPAR isotypes to energy homeostasis","volume":"127","author":"Dubois","year":"2017","journal-title":"J Clin Invest."},{"issue":"28","key":"2022020904394333200_CIT0022","doi-asserted-by":"crossref","first-page":"25468","DOI":"10.1074\/jbc.M301302200","article-title":"The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element","volume":"278","author":"Prieur","year":"2003","journal-title":"J Biol Chem."},{"issue":"5","key":"2022020904394333200_CIT0023","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/j.jcmgh.2021.01.012","article-title":"Transcriptional regulation of metabolic pathways via lipid-sensing nuclear receptors PPARs, FXR, and LXR in NASH","volume":"11","author":"Cariello","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol."},{"issue":"1","key":"2022020904394333200_CIT0024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2009.03.008","article-title":"Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease","volume":"205","author":"Fruchart","year":"2009","journal-title":"Atherosclerosis."},{"issue":"4","key":"2022020904394333200_CIT0025","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1161\/01.ATV.0000054194.78240.45","article-title":"Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice","volume":"23","author":"Pennacchio","year":"2003","journal-title":"Arterioscler Thromb Vasc Biol."},{"issue":"20","key":"2022020904394333200_CIT0026","first-page":"3895","article-title":"Atorvastatin might inhibit insulin resistance induced by insulin through the triglyceride-lowering role of apolipoprotein AV","volume":"19","author":"Zao","year":"2015","journal-title":"Eur Rev Med Pharmacol Sci."},{"issue":"2","key":"2022020904394333200_CIT0027","doi-asserted-by":"crossref","first-page":"e0149681","DOI":"10.1371\/journal.pone.0149681","article-title":"Alagille syndrome candidates for liver transplantation: differentiation from end-stage biliary atresia using preoperative CT","volume":"11","author":"Hwang","year":"2016","journal-title":"PLoS One."}],"container-title":["Journal of the Endocrine Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jes\/advance-article-pdf\/doi\/10.1210\/jendso\/bvac005\/42234392\/bvac005.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jes\/article-pdf\/6\/3\/bvac005\/42436468\/bvac005.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jes\/article-pdf\/6\/3\/bvac005\/42436468\/bvac005.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T04:55:20Z","timestamp":1644382520000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jes\/article\/doi\/10.1210\/jendso\/bvac005\/6511002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,18]]},"references-count":27,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jendso\/bvac005","relation":{},"ISSN":["2472-1972"],"issn-type":[{"value":"2472-1972","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,3,1]]},"published":{"date-parts":[[2022,1,18]]},"article-number":"bvac005"}}