Original Article
Ezetimibe Reduces Plant Sterol Accumulation and Favorably Increases Platelet Count in Sitosterolemia

https://doi.org/10.1016/j.jpeds.2014.08.069Get rights and content

Objective

To assess if ezetimibe (EZE), a sterol-absorption inhibitor, improves platelet (PLT) count and size relative to its effect on plasma plant sterol (PS) in patients with sitosterolemia (STSL).

Study design

Patients with STSL (5 males, 3 females, 16-56 years of age) receiving EZE intervention as part of their routine care participated in this study. EZE was discontinued for 14 weeks (off) and then resumed for another 14 weeks (on). Hematology variables along with plasma and red blood cells (RBC) PS and total cholesterol (TC) levels were measured at the end of each phase.

Results

EZE increased PLT count (23% ± 9%) and decreased mean PLT volume (MPV; 10% ± 3%, all P < .05). In patients off EZE, PLT counts inversely correlated (r = −0.96 and r = −0.91, all P < .01) with plasma and RBC PS to TC ratio (PS/TC), and MPV positively correlated (r = 0.91, P = .03 and r = 0.93, P = .02) with plasma and RBC PS/TC. EZE reduced plasma and RBC sitosterol (−35% ± 4% and −28% ± 3%), total PS (−37% ± 4% and −28% ± 3%, all P < .0001) levels, and PS/TC (−27% ± 4% and −28% ± 4%, P < .01).

Conclusions

EZE reduces plasma and RBC PS levels, while increasing PLT count and decreasing MPV, and thereby may reduce the risk for bleeding in STSL. Plasma PS levels and ABCG5/ABCG8 genes should be analyzed in patients with unexplained hematologic abnormalities.

Section snippets

Methods

Eight patients (5 males and 3 females, between 16 and 56 years of age) were recruited from Hutterite colonies in Manitoba, Canada (n = 4) and South Dakota, US (n = 4). All patients were identified as having homozygous ABCG8 S107X mutation (NM_022437.2:c.320C>G) and are related to a proband previously reported by Mymin et al21, 22 and Chong et al.23 All procedures involving human patients were approved by the University of Manitoba Biomedical Ethics board and written informed consent was

Results

All 8 initially recruited patients completed the study (Table I). Mean values of serum TC and LDL-cholesterol indicated mild hypercholesterolemia. All patients had elevated plasma and RBC levels of PS (Table I). The plasma and RBC concentrations of sitosterol and total PS were similar on average (P > .11), but the PS to TC ratio (PS/TC) tended to be higher in RBC than in plasma (P = .08; Table I). One subject had mild anemia (hemoglobin [Hb] = 11.7 g/dL; hematocrit = 37.7%), and stomatocytes

Discussion

The major finding of this study is that blocking intestinal absorption of PS with EZE in patients with STSL increases PLT number and decreases PLT size, and measures were correlated with reductions in blood PS concentrations. The minimal effect of EZE on blood cholesterol suggests that the improvements in PLT count and size were primarily because of improved PS homeostasis. The effect of EZE on PLT may potentially ameliorate the bleeding tendency in STSL.

Mutations in ABCG5/8 genes cause STSL,

References (43)

Cited by (35)

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    Citation Excerpt :

    In their clinical trial, Lütjohann et al. found no decrease (in point of fact a 2% increase) in cholesterol levels [6]. In a recent study by Othman et al., only a small 12% cholesterol decrease was found [7]. With respect to sitosterol levels similar, if less stark, differences exist compared to our cohort.

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Supported by the Canadian Institutes of Health Research (MOP12339). The Sterol and Isoprenoid Research (STAIR; U54HD061939) Consortium is a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network, supported through collaboration between the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science, and National Institute of Child Health and Human Development. R.O. was supported by the Libyan Scholarship Program and the Manitoba Health Research Council Graduate Student Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors declare no conflicts of interest.

Registered with www.ClinicalTrials.gov: NCT01584206.

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