Vuorio Alpo, Kuoppala Jaana, Kovanen Petri T, Humphries Steve E, Tonstad Serena, Wiegman Albert, Drogari Euridiki, Ramaswami Uma
University of Helsinki, Department of Forensic Medicine, Helsinki, Finland.
University of Helsinki, Helsinki, Finland.
Cochrane Database Syst Rev. 2019 Nov 7;2019(11):CD006401. doi: 10.1002/14651858.CD006401.pub5.
Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review.
To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia.
Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline. Date of most recent search: 04 November 2019.
Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone.
Two authors independently assessed studies for inclusion and extracted data.
We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (high-quality evidence). There may be little or no difference in liver function (serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations) between treated and placebo groups at any time point (low-quality evidence). There may be little or no difference in myopathy (as measured in change in creatinine levels) (low-quality evidence) or clinical adverse events (moderate-quality evidence) with statins compared to placebo. One study on simvastatin showed that this may slightly improve flow-mediated dilatation of the brachial artery (low-quality evidence), and on pravastatin for two years may have induced a regression in carotid intima media thickness (low-quality evidence). No studies reported rhabdomyolysis (degeneration of skeletal muscle tissue) or death due to rhabdomyolysis, quality of life or compliance to study medication.
AUTHORS' CONCLUSIONS: Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. Few or no safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.
家族性高胆固醇血症是最常见的遗传性代谢疾病之一，是一种常染色体显性疾病，这意味着杂合子或携带者会受到影响。纯合子患者病情严重。全球杂合子家族性高胆固醇血症的平均患病率至少为五百分之一，不过丹麦最近的基因流行病学数据和下一代测序数据表明，实际患病率可能更接近二百五十分之一。儿童家族性高胆固醇血症的诊断基于总胆固醇和低密度脂蛋白胆固醇水平升高，或基于DNA的分析，或两者结合。在年仅17岁的杂合子家族性高胆固醇血症男性以及25岁的杂合子家族性高胆固醇血症女性中都检测到了冠状动脉粥样硬化。由于动脉粥样硬化的临床并发症过早出现，尤其是在男性中，因此需要从儿童期开始进行终身治疗，以降低心血管疾病风险。对于患有该疾病的儿童，饮食是治疗的基石，但添加降脂药物已使治疗效果有了显著改善。发现阴离子交换树脂，如消胆胺和考来替泊，是有效的，但耐受性较差。自20世纪90年代以来，对6至17岁的杂合子家族性高胆固醇血症儿童进行的研究表明，他们的血清总胆固醇和低密度脂蛋白胆固醇水平有显著降低。虽然他汀类药物在儿童中似乎安全且耐受性良好，但该年龄组的长期安全性尚未得到确证。这是对该Cochrane综述先前发表版本的更新。
评估他汀类药物对杂合子家族性高胆固醇血症儿童的有效性和安全性。
从该组织的先天性代谢缺陷试验注册库和Medline中识别相关研究。最近一次检索日期：2019年11月4日。
随机对照临床研究，参与者年龄不超过18岁，比较他汀类药物与安慰剂或单纯饮食。
两位作者独立评估研究是否纳入并提取数据。
我们发现了26项可能符合条件的研究，其中我们纳入了9项随机安慰剂对照研究（1177名参与者）。总体而言，干预和随访时间较短（中位数为24周；范围为6周至2年）。他汀类药物在所有时间点均降低了平均低密度脂蛋白胆固醇浓度（高质量证据）。在任何时间点，治疗组和安慰剂组之间的肝功能（血清天冬氨酸和丙氨酸转氨酶以及肌酸激酶浓度）可能几乎没有差异或没有差异（低质量证据）。与安慰剂相比，他汀类药物在肌病（以肌酐水平变化衡量）（低质量证据）或临床不良事件（中等质量证据）方面可能几乎没有差异或没有差异。一项关于辛伐他汀的研究表明，这可能会轻微改善肱动脉的血流介导的扩张（低质量证据），而普伐他汀治疗两年可能会使颈动脉内膜中层厚度有所消退（低质量证据）。没有研究报告横纹肌溶解（骨骼肌组织退化）或因横纹肌溶解导致的死亡、生活质量或对研究药物的依从性。
他汀类药物治疗是家族性高胆固醇血症儿童有效的降脂疗法。几乎未发现或未发现安全问题。他汀类药物治疗在短期内似乎是安全的，但长期安全性仍然未知。接受他汀类药物治疗的儿童应由儿科医生仔细监测和随访，一旦年满18岁，其护理应转交给成人脂质专家。需要进行大型长期随机对照试验来确定他汀类药物的长期安全性问题。
