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.

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.

Figure 1.. Survival.

Kaplan-Meier survival curves are shown for patients with a) ferritin levels above and below 1,000 μg/L and b) patients with direct bilirubin levels above and below 0.4 mg/dL. P-values were calculated using the log-rank test. In figure 1a, patients with elevated ferritin greater than 1000 μg/L had a lower rate of survival compared with those who had ferritin levels less than 1000 μg/L. In figure 1b, patients with elevated direct bilirubin levels above 0.4 mg/dL had a lower rate of survival compared with those who had direct bilirubin levels below 0.4 mg/dL.

Figure 1.. Survival.

Kaplan-Meier survival curves are shown for patients with a) ferritin levels above and below 1,000 μg/L and b) patients with direct bilirubin levels above and below 0.4 mg/dL. P-values were calculated using the log-rank test. In figure 1a, patients with elevated ferritin greater than 1000 μg/L had a lower rate of survival compared with those who had ferritin levels less than 1000 μg/L. In figure 1b, patients with elevated direct bilirubin levels above 0.4 mg/dL had a lower rate of survival compared with those who had direct bilirubin levels below 0.4 mg/dL.