{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:46:39Z","timestamp":1762004799739},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,4,15]],"date-time":"2016-04-15T00:00:00Z","timestamp":1460678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Bilirubin has anti\u2010oxidative and anti\u2010inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation <jats:italic>in vitro<\/jats:italic>, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>A randomized double\u2010blind cross\u2010over study (ClinicalTrials.gov, number <jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>01546992) was performed in 47 patients with secondary adrenal failure [10\u2010week exposure to a higher hydrocortisone dose (0\u00b74\u20130\u00b76 mg\/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0\u00b72\u20130\u00b73 mg\/kg body weight)].<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Plasma total bilirubin was increased by 10% from 7 to 8 \u03bcM in response to the higher hydrocortisone dose (<jats:italic>P<\/jats:italic> = 0\u00b7033). This effect was inversely related to age (<jats:italic>P<\/jats:italic> = 0\u00b7042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (<jats:italic>P<\/jats:italic> = 0\u00b7006) and aspartate aminotransferase activities (<jats:italic>P<\/jats:italic> = 0\u00b7001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro\u2010inflammatory state and enhanced liver fat accumulation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.12624","type":"journal-article","created":{"date-parts":[[2016,3,22]],"date-time":"2016-03-22T01:10:59Z","timestamp":1458609059000},"page":"475-480","source":"Crossref","is-referenced-by-count":6,"title":["Higher hydrocortisone dose increases bilirubin in hypopituitary patients\u2010 results from an <scp>RCT<\/scp>"],"prefix":"10.1111","volume":"46","author":[{"given":"Jorien","family":"Werumeus Buning","sequence":"first","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny E.","family":"Kootstra\u2010Ros","sequence":"additional","affiliation":[{"name":"Laboratory Center University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Brummelman","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerrit","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"van der Klauw","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce H. R.","family":"Wolffenbuttel","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9 P.","family":"van Beek","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin P. F.","family":"Dullaart","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,4,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"16712","DOI":"10.1016\/S0021-9258(19)89449-8","article-title":"Free and albumin\u2010bound bilirubin are efficient co\u2010antioxidants for alpha\u2010tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation","volume":"269","author":"Neuzil J","year":"1994","journal-title":"J Biol Chem"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.06.029"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20140566"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm.2011.662"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475\u20102840\u201012\u2010166"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2015.06.016"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000091966"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2012.08.029"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.114066"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304929"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/604981"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2015.09.003"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(96)00184-9"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(96)00183-2"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(99)00439-4"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.0135"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2015.02.001"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2009.02234.x"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(59)90310-9"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.328.7441.702"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2013.07.013"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:MOLE.0000043582.35335.ff"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-005-1750-9"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195707112570204"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.83.4.1247"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2010.052"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132822"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2015.09.002"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1530\/eje.0.1490543"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2015.07.020"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2003.07486.x"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2003.07485.x"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037241"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvg188"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090886"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Feci.12624","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.12624","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/eci.12624","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.12624","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T22:41:05Z","timestamp":1695508865000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.12624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,15]]},"references-count":35,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,5]]}},"alternative-id":["10.1111\/eci.12624"],"URL":"https:\/\/doi.org\/10.1111\/eci.12624","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"value":"0014-2972","type":"print"},{"value":"1365-2362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,15]]}}}