LDL-cholesterol variability and cardiovascular follow-Up in sitosterolemia

Abstract Background Sitosterolemia is a rare autosomal recessive disorder caused by biallelic mutations in ABCG5 and ABCG8, leading to abnormal accumulation of plant sterols. Clinically, it is often characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, xanthomas, and an increased risk of premature atherosclerosis. Although a plant sterol-free diet and ezetimibe are established therapies, data on the clinical follow-up of these patients remain scarce. Purpose This study aimed to evaluate LDL-C variability and cardiovascular follow-up in a series of patients with sitosterolemia. Methods We analyzed patients with genetically and biochemically confirmed sitosterolemia from a database of a specialized cardiovascular center. Consecutive measurements of lipid parameters and longitudinal data on clinical and subclinical cardiovascular disease were collected. Data were represented as means ± standard deviation or percentages. Results From a genotyping program of hypercholesterolemic patients, we identified 12 patients with a confirmed diagnosis of sitosterolemia who had at least one consultation at our lipid clinic, beginning in 2012. Our cohort comprised 50% females (n = 6) with a mean age of 42 ± 15.89 years (Table). Except for a 3-year-old child, all patients started ezetimibe therapy and received specific dietary guidance along with statins soon after their first consultation and diagnosis. Despite these recommendations, there was striking variability in LDL-C measurements during follow-up (Figure), with a difference of 68.8% between the highest and lowest mean LDL-C values in this cohort. Regarding cardiovascular outcomes, 10 patients had atherosclerotic cardiovascular disease (ASCVD), with only one case being subclinical (high coronary artery calcium score), while all others presented clinically. Two patients developed ischemic cardiomyopathy, and one died. Interestingly, among the 10 patients who underwent echocardiography, only one had aortic valve calcification, and this patient had a history of rheumatic fever. Conclusion Sitosterolemia is a rare genetic disease often misdiagnosed as familial hypercholesterolemia due to the typically high LDL-C levels, xanthomas, and premature atherosclerosis. However, the dramatic fluctuations in LDL-C levels, the early onset of coronary disease, and the absence of aortic valve calcification highlight the unique characteristics of this condition and the need for personalized therapies. Poor adherence to diet and pharmacological treatments may have contributed to this variability. Whether LDL-C measurement is an appropriate tool for monitoring these patients remains unclear. Further studies are required to assess long-term cardiovascular outcomes in this population.Table Figure