Arvanitakis Konstantinos, Chatzikalil Elena, Antza Christina, Topalidis Christos, Kalopitas Georgios, Solomou Elena, Kotsis Vasilios, Germanidis Georgios, Koufakis Theocharis, Doumas Michael
Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece.
Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece.
Nutrients. 2025 Jul 18;17(14):2357. doi: 10.3390/nu17142357.
Familial hypercholesterolemia (FH) is a genetic disorder marked by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) since childhood, substantially increasing the risk of premature atherosclerosis and cardiovascular disease. While dysfunction of hepatic LDL-C receptors is the main underlying cause, the gastrointestinal tract plays a key role in cholesterol homeostasis and represents an important therapeutic target. Inhibition of intestinal cholesterol absorption has emerged as an effective strategy in the management of pediatric FH, particularly in patients for whom statins may not be the ideal first-line treatment. Ezetimibe, an inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) protein, has been shown to reduce LDL-C levels in children with FH, with a greater efficacy observed when used in combination with statins. Bile acid sequestrants also enhance cholesterol excretion but are often limited by gastrointestinal side effects, while dietary interventions, such as phytosterol supplementation and fiber-enriched diets, provide additional benefits in lowering LDL-C and are generally well tolerated. Emerging therapies, including microbiota-targeted strategies and novel cholesterol absorption inhibitors, show promise for expanding future treatment options. This review explores the mechanisms of intestinal cholesterol absorption and their relevance to pediatric FH. We examine key pathways, including dietary cholesterol uptake through NPC1L1, bile acid reabsorption, and cholesterol efflux mediated by ATP-binding cassette transporters, while also discussing clinical and experimental evidence on pharmacological and dietary interventions that modulate these pathways. A deeper understanding of cholesterol metabolism, the emerging role of the gut microbiota, and innovative therapeutic agents can support the development of more effective and personalized approaches to the treatment of children with FH.
家族性高胆固醇血症（FH）是一种遗传性疾病，其特征是自儿童期起低密度脂蛋白胆固醇（LDL-C）水平显著升高，大大增加了早发性动脉粥样硬化和心血管疾病的风险。虽然肝脏LDL-C受体功能障碍是主要潜在原因，但胃肠道在胆固醇稳态中起关键作用，是一个重要的治疗靶点。抑制肠道胆固醇吸收已成为治疗儿童FH的有效策略，特别是对于他汀类药物可能不是理想一线治疗药物的患者。依折麦布是一种尼曼-匹克C1样1（NPC1L1）蛋白抑制剂，已被证明可降低FH儿童的LDL-C水平，与他汀类药物联合使用时疗效更佳。胆汁酸螯合剂也可增强胆固醇排泄，但常受胃肠道副作用限制，而饮食干预，如补充植物甾醇和富含纤维的饮食，在降低LDL-C方面有额外益处，且通常耐受性良好。包括针对微生物群的策略和新型胆固醇吸收抑制剂在内的新兴疗法，有望扩展未来的治疗选择。本综述探讨了肠道胆固醇吸收的机制及其与儿童FH的相关性。我们研究了关键途径，包括通过NPC1L1摄取膳食胆固醇、胆汁酸重吸收以及由ATP结合盒转运蛋白介导的胆固醇流出，同时还讨论了调节这些途径的药物和饮食干预的临床和实验证据。对胆固醇代谢、肠道微生物群的新作用以及创新治疗药物的更深入理解，可以支持开发更有效和个性化的方法来治疗FH儿童。
