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At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca<jats:sup>2+<\/jats:sup> influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic> findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, patients with hyperbilirubinemia had significantly lower erythrocyte and significantly higher reticulocyte counts compared to patients with low bilirubin levels. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease. (H<jats:sc>epatology<\/jats:sc> 2015;61:275\u2013284)<\/jats:p>","DOI":"10.1002\/hep.27338","type":"journal-article","created":{"date-parts":[[2014,7,28]],"date-time":"2014-07-28T09:08:54Z","timestamp":1406538534000},"page":"275-284","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":87,"title":["Conjugated bilirubin triggers anemia by inducing erythrocyte death"],"prefix":"10.1097","volume":"61","author":[{"given":"Elisabeth","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases,University of D\u00fcsseldorf,D\u00fcsseldorf,Germany"},{"name":"Department of Physiology,University of T\u00fcbingen,T\u00fcbingen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergios","family":"Gatidis","sequence":"additional","affiliation":[{"name":"Department of Physiology,University of 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