title: Liver injury is associated with mortality in sickle cell disease.
abstract: BACKGROUND
  Increased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso-occlusion and chronic haemolysis to multiple organ systems.
  
  
  OBJECTIVE
  To report the long-term consequences of liver dysfunction in SCD.
  
  
  METHODS
  A cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression.
  
  
  RESULTS
  Exactly, 247 SCD patients were followed up for 30 months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension.
  
  
  CONCLUSIONS
  Ferritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults.
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.|Toronto Centre for Liver Disease, Sandra Rotman Center for Global Health, University of Toronto, Toronto, ON, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Feld
authors.affiliation: National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.|Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Kato
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Koh
authors.affiliation: National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Shields
authors.affiliation: National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hildesheim
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Taylor
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Sandler
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Douek
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Haynes-Williams
authors.affiliation: National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Nichols
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Hoofnagle
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Jake Liang
authors.affiliation: National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.|Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Heller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000401:mortality*; D005260:Female; D005293:Ferritins / Q000097:blood; D006801:Humans; D007501:Iron / Q000097:blood; D019190:Iron Overload / Q000097:blood / Q000150:complications / Q000401:mortality; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications / Q000401:mortality; D008107:Liver Diseases / Q000097:blood / Q000150:complications* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D005293:Ferritins; D007501:Iron