title: Conjugated bilirubin triggers anemia by inducing erythrocyte death.
abstract: Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver-damaging diseases, such as infection and alcohol intoxication. 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(2+) influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo 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.
  
  
  CONCLUSIONS
  Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease.
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany; Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Elisabeth
authors: E
authors: Lang
authors: Sergios
authors: S
authors: Gatidis
authors: Noemi F
authors: NF
authors: Freise
authors: Hans
authors: H
authors: Bock
authors: Ralf
authors: R
authors: Kubitz
authors: Christian
authors: C
authors: Lauermann
authors: Hans Martin
authors: HM
authors: Orth
authors: Caroline
authors: C
authors: Klindt
authors: Maximilian
authors: M
authors: Schuier
authors: Verena
authors: V
authors: Keitel
authors: Maria
authors: M
authors: Reich
authors: Guilai
authors: G
authors: Liu
authors: Sebastian
authors: S
authors: Schmidt
authors: Haifeng C
authors: HC
authors: Xu
authors: Syed M
authors: SM
authors: Qadri
authors: Diran
authors: D
authors: Herebian
authors: Aleksandra A
authors: AA
authors: Pandyra
authors: Ertan
authors: E
authors: Mayatepek
authors: Erich
authors: E
authors: Gulbins
authors: Florian
authors: F
authors: Lang
authors: Dieter
authors: D
authors: Häussinger
authors: Karl S
authors: KS
authors: Lang
authors: Michael
authors: M
authors: Föller
authors: Philipp A
authors: PA
authors: Lang
mesh_terms: D000368:Aged; D000740:Anemia / Q000209:etiology*; D000818:Animals; D001663:Bilirubin / Q000097:blood*; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D016923:Cell Death; D004912:Erythrocytes / Q000502:physiology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D017093:Liver Failure / Q000097:blood / Q000150:complications*; D008297:Male; D051379:Mice; D008875:Middle Aged; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D013108:Sphingomyelin Phosphodiesterase; D001663:Bilirubin; D002118:Calcium