J J Feld1,2, G J Kato3,4, C Koh1, T Shields3, M Hildesheim3, D E Kleiner5, J G Taylor3, N G Sandler6, D Douek6, V Haynes-Williams1, J S Nichols3, J H Hoofnagle1, T Jake Liang1, M T Gladwin3,4, T Heller1. 1. Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA. 2. Toronto Centre for Liver Disease, Sandra Rotman Center for Global Health, University of Toronto, Toronto, ON, Canada. 3. National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA. 4. Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 5. Laboratory of Pathology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA. 6. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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. AIM: 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. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
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. AIM: To report the long-term consequences of liver dysfunction in SCD. METHODS: A cohort of SCDpatients 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 SCDpatients 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. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
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