TREATMENT OF FAMILIAL HYPERCHOLESTEROLEMIA BY DEXTRAN SULFATE APHERESIS

家族性高胆固醇血症（FH） IIa型患者由于低密度脂蛋白（LDL）和Lp(a)胆固醇水平升高而具有早发冠状动脉疾病的高风险。饮食和药物治疗可以降低大多数杂合子FH患者的胆固醇浓度，但一小部分杂合子和几乎所有纯合子对治疗没有反应。在一项美国多中心合作研究中，对这些患者通过硫酸葡聚糖亲和吸附选择性去除LDL进行了评估。葡聚糖硫酸盐分离系统（Liposorber LA-15, Kaneka, Japan）去除LDL和Lp(a)而不降低HDL或白蛋白水平，从而避免了胶体替代溶液的需要。临床中心招募了6名FH患者；在全国范围内纳入的总队列包括10个纯合子和54个杂合子。治疗每隔7- 14天进行一次。在纯合子中，总胆固醇、LDL和Lp(a)水平的平均急性降低分别为70%、81%和68%，在杂合子中分别为61%、76%和65%。这些治疗的耐受性很好。多中心研究结果表明，硫酸葡聚糖吸附是一种安全有效的清除血浆中LDL胆固醇的方法，与简单的血浆交换相比，其优点是不需要胶体替代溶液。本研究收集的数据被用作LA-15系统许可的基础，该系统于1996年7月被FDA批准用于治疗FH。目前，患者正在LDL-Apheresis登记处继续进行长期随访，以收集许可后长期治疗对原发性和继发性动脉粥样硬化事件发展的影响以及对总生存期的影响。对最初64例接受长期ldl分离的患者中的49例进行了为期5年的中期分析。在接受LDL-apheresis治疗的5年期间，心血管事件的发生率比接受LDL-apheresis治疗前的5年期间降低了44%（每1000个月治疗3.5个事件，而LDL-apheresis治疗前为6.3个事件）。这些发现支持LDL采珠术对药物治疗控制不充分的FH患者的长期安全性和临床疗效。两名患者继续在临床中心接受常规的两周低密度脂蛋白分离治疗，而第三名患者，一名儿童，每两周接受血浆交换，直到他的血容量大到足以耐受低密度脂蛋白分离装置的体外容量。

Patients with familial hypercholesterolemia (FH) type IIa are at high risk of premature coronary artery disease due to elevated low density lipoprotein (LDL) and Lp(a) cholesterol levels. Diet and drug therapy can reduce cholesterol concentrations in most patients with heterozygous FH, but a small proportion of heterozygotes and nearly all homo-zygotes do not respond to therapy. Selective removal of LDL by dextran sulfate affinity adsorption was evaluated in these patients in a collaborative multicenter U.S. study. The dextran sulfate apheresis system (Liposorber LA-15, Kaneka, Japan) removed LDL and Lp(a) without lowering HDL or albumin levels, thus avoiding the need for colloid replacement solutions. Six FH patients were enrolled at the Clinical Center; the total cohort enrolled nationwide included 10 homozygotes and 54 heterozygotes. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in total, LDL, and Lp(a) cholesterol levels were 70 percent, 81 percent, and 68 percent, respectively, in homozygotes and 61 percent, 76 percent, and 65 percent, respectively, in heterozygotes. The treatments were very well tolerated. The results of the multicenter study suggest that dextran sulfate adsorption is a safe and effective way to clear plasma of LDL cholesterol and has the advantage, compared to simple plasma exchange, of eliminating the need for colloid replacement solutions. The data gathered in this study were used as the basis for licensure of the LA-15 system, which was approved by the FDA for treatment of FH in July 1996. Patients are now continu- ing long-term follow-up on an LDL-Apheresis Registry to gather post- licensure data on the effect of long-term treatment on development of primary and secondary atherosclerotic events, and on overall survival. A 5-year interim analysis of 49 of the original 64 patients who received long-term LDL-apheresis was performed. There was a 44 percent reduction in cardiovascular events during the 5 years the patients received LDL-apheresis compared with the 5-year period prior to LDL apheresis (3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months before LDL-apheresis therapy). These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with FH who are inadequately controlled with drug therapy. Two patients are continuing to receive regular biweekly LDL apheresis treatments at the Clinical Center, while a third patient, a child, receives biweekly plasma exchange until his blood volume becomes large enough to tolerate the extracorporeal volume of the LDL apheresis device.