Sitosterolemia as a treatable and underrecognized cause of chronic thrombocytopenia beyond ITP: A targeted screening study

BACKGROUND: Sitosterolemia is a rare autosomal recessive lipid disorder traditionally associated with hypercholesterolemia and xanthomas. However, hematologic abnormalities such as chronic thrombocytopenia and hemolytic anemia are increasingly recognized, often resulting in delayed diagnosis and inappropriate management. OBJECTIVE: This study aims to assess the effectiveness of a targeted screening strategy for identifying sitosterolemia in patients with unexplained hematologic abnormalities and to define associated clinical features and treatment response. METHODS: In this multicenter, cross-sectional study, 100 patients with unexplained chronic thrombocytopenia, nonimmune hemolytic anemia, or abnormal erythrocyte morphology and 54 healthy controls were evaluated. Plasma sitosterol levels were measured after ≥8 hours of fasting. Patients with elevated levels (>15 mg/L) underwent repeat testing, exclusion of secondary causes, and molecular analysis of ABCG5/ABCG8 genes. RESULTS: Elevated sitosterol levels were detected in 15 patients, of whom 9 had persistent elevation and underwent genetic testing. Sitosterolemia was confirmed in 7 patients, yielding a detection rate of 7% in this at-risk cohort. Consanguinity, xanthomas, and elevated transaminases were significantly associated with sitosterolemia. Notably, dyslipidemia was not consistently present. Treatment with ezetimibe and a plant sterol-restricted diet resulted in significant improvement in platelet counts and reduction in Low-density lipoprotein cholesterol levels, along with normalization of peripheral blood smear findings. CONCLUSION: Sitosterolemia is an underrecognized but treatable cause of hematologic abnormalities. Targeted screening in patients with unexplained cytopenias can improve detection. Early diagnosis enables effective treatment, leading to reversal of hematologic findings and reduction of long-term cardiovascular risk.