Hypocholesterolemia in a Large Sickle Cell Cohort: Correlations of Serum Lipids to Markers of Intravascular Hemolysis and Vascular Dysfunction

Background: Hypocholesterolemia in sickle cell disease (SCD) has been documented in small cohorts from Nigeria, Cameron, Iran and the United States. Although not uniformly consistent, these studies found decreased total plasma cholesterol levels, HDL- cholesterol (HDL-C) and LDL-cholesterol (LDL-C), when compared to healthy controls. Consistent with the low levels of LDL-C, atherosclerosis is largely absent in SCD patients. However, vascular dysfunction is prevalent, and higher-than-average triglyceride (TG) levels, a known risk factor for vascular diseases, have also been reported in SCD populations.

Methods: In a large SCD cohort, consisting of 405 SCD patients with normal and mildto- significantly elevated pulmonary artery pressures (tricuspid regurgitant jet velocities (TRVs) ranging from 1 to 4.9) as well as 32 healthy African American controls, we determined mean serum lipid levels for total cholesterol, HDL-C, LDL-C and TG. We also determined apolipoprotein levels, ApoA-I, ApoB and the ratio ApoA-I/ApoB. We then investigated the correlations between plasma serum lipids and apolipoproteins against a battery of markers of intravascular hemolysis and vascular dysfunction.

Results: In our large cohort, we observe significantly lower mean total cholesterol levels in SCD patients versus healthy controls (135.2 and 187.5 mg/dL, respectively, p<0.001). Total serum cholesterol was negatively correlated to markers of intravascular hemolysis (absolute reticulocyte count, p<0.0001; total bilirubin, p<0.0001, indirect bilirubin, p<0.0001), and positively associated with hemoglobin and hematocrit (p=0.0036 and p=0.0028, respectively). Mean HDL-C levels were statistically significantly lower in the SCD cohort versus healthy controls (41.27 and 58.91, respectively, p<0.0001), and were also negatively correlated to absolute reticulocyte count (p< 0.0001), total bilirubin (p<0.0001) as well as to LDH, another well-known marker of intravascular hemolysis (p<0.0001). Mean LDL-C levels were significantly lower in SCD patients than in control subjects (78.22 and 117.1 mg/dL, respectively, p<0.0001), and were negatively correlated to reticulocyte count (p=0.0002), and total bilirubin (p= 0.0025).

In contrast, mean triglyceride levels were significantly higher in the SCD cohort than in healthy subjects (123.2 vs. 76.42 mg/dL respectively, p<0.0001), and were inversely correlated to hemoglobin (p= 0.0005) and hematocrit (p= 0.0003). TGs were also significantly positively correlated to markers of hemolysis: plasma hemoglobin (p= 0.0004), LDH (p= 0.0005), and with arginase (p=0.003), ornithine (p< 0.0001), and SE selectin (p= 0.0386). Moreover, when the SCD cohort was divided among low-TRV (<2.5), moderate-TRV (2.5–2.9) or high-TRV (>2.9) cohorts, the mean plasma TG levels were significantly different between the low and high TRV groups. Specifically, for low-TRV patients (TRV<2.5, n=197), the mean plasma TG level was 110.5 mg/dL (95% confidence interval 102.5–118.6, median 102.0); for moderate-TRV patients (TRV=2.5–2.9, n=103) the mean TG level did not differ significantly from the low-TRV group (TG=115.3 mg/dL, 95% CI 104.6–126.1; median 105.0); however, for high TRV patients (TRV>2.9, n = 58), the TG mean was significantly higher (153.4, 95% CI 131.4–175.5, median=136.0). Interestingly, ApoA-I levels were also low in SCD patients, and there was a trend towards lower ApoA-I levels in the higher TRV patient groups, but this trend did not achieve statistical significance. Lastly, ApoA-I levels were significantly positively correlated with NTProBNP, a marker of pulmonary hypertension (p= 0.0026).

Conclusions: To our knowledge, this constitutes the first evidence that hypocholesterolemia in sickle cell disease is correlated with markers of intravascular hemolysis and vascular dysfunction. Further study is needed to explore the mechanistic basis for these correlations; however, one possibility is that the fatty acids carried by triglycerides may become oxidized in SCD patients with hemolytic oxidative stress and serve as signaling molecules, or alternatively, hemolytic oxidative stress may coordinately regulate these pathways. Our findings provide a link between plasma lipids, particularly triglyceride levels, and vascular dysfunction in sickle cell disease.