Liver injury is associated with mortality in sickle cell disease

J. J. Feld, G. J. Kato, C. Koh, T. Shields, M. Hildesheim, D. E. Kleiner, J. G. Taylor, N. G. Sandler, D. Douek, V. Haynes-Williams, J. S. Nichols, J. H. Hoofnagle, T. Jake Liang, M. T. Gladwin, T. Heller

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)912-921
Number of pages10
JournalAlimentary Pharmacology and Therapeutics
Volume42
Issue number7
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

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Sickle Cell Anemia
Ferritins
Mortality
Liver
Wounds and Injuries
Bilirubin
Iron Overload
Venous Pressure
Portal Hypertension
Hemolysis
Fibrosis
National Institutes of Health (U.S.)
Left Ventricular Dysfunction
Life Expectancy
Bile Acids and Salts
Platelet Count
Blood Transfusion
Liver Cirrhosis
Alkaline Phosphatase
Echocardiography

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Feld, J. J., Kato, G. J., Koh, C., Shields, T., Hildesheim, M., Kleiner, D. E., ... Heller, T. (2015). Liver injury is associated with mortality in sickle cell disease. Alimentary Pharmacology and Therapeutics, 42(7), 912-921. https://doi.org/10.1111/apt.13347

Liver injury is associated with mortality in sickle cell disease. / Feld, J. J.; Kato, G. J.; Koh, C.; Shields, T.; Hildesheim, M.; Kleiner, D. E.; Taylor, J. G.; Sandler, N. G.; Douek, D.; Haynes-Williams, V.; Nichols, J. S.; Hoofnagle, J. H.; Jake Liang, T.; Gladwin, M. T.; Heller, T.

In: Alimentary Pharmacology and Therapeutics, Vol. 42, No. 7, 01.10.2015, p. 912-921.

Research output: Contribution to journalArticle

Feld, JJ, Kato, GJ, Koh, C, Shields, T, Hildesheim, M, Kleiner, DE, Taylor, JG, Sandler, NG, Douek, D, Haynes-Williams, V, Nichols, JS, Hoofnagle, JH, Jake Liang, T, Gladwin, MT & Heller, T 2015, 'Liver injury is associated with mortality in sickle cell disease', Alimentary Pharmacology and Therapeutics, vol. 42, no. 7, pp. 912-921. https://doi.org/10.1111/apt.13347
Feld JJ, Kato GJ, Koh C, Shields T, Hildesheim M, Kleiner DE et al. Liver injury is associated with mortality in sickle cell disease. Alimentary Pharmacology and Therapeutics. 2015 Oct 1;42(7):912-921. https://doi.org/10.1111/apt.13347
Feld, J. J. ; Kato, G. J. ; Koh, C. ; Shields, T. ; Hildesheim, M. ; Kleiner, D. E. ; Taylor, J. G. ; Sandler, N. G. ; Douek, D. ; Haynes-Williams, V. ; Nichols, J. S. ; Hoofnagle, J. H. ; Jake Liang, T. ; Gladwin, M. T. ; Heller, T. / Liver injury is associated with mortality in sickle cell disease. In: Alimentary Pharmacology and Therapeutics. 2015 ; Vol. 42, No. 7. pp. 912-921.
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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.",
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T1 - Liver injury is associated with mortality in sickle cell disease

AU - Feld, J. J.

AU - Kato, G. J.

AU - Koh, C.

AU - Shields, T.

AU - Hildesheim, M.

AU - Kleiner, D. E.

AU - Taylor, J. G.

AU - Sandler, N. G.

AU - Douek, D.

AU - Haynes-Williams, V.

AU - Nichols, J. S.

AU - Hoofnagle, J. H.

AU - Jake Liang, T.

AU - Gladwin, M. T.

AU - Heller, T.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

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