低密度脂蛋白胆固醇定量方法的改进
Author: Jing Cao, PhD, DABCC, Assistant Professor, Department of Pathology, University of Texas Southwestern Medical Center
Low-density lipoprotein cholesterol (LDL-C) has always been a key indicator in the guidelines for risk assessment, prevention, and treatment monitoring of atherosclerotic cardiovascular disease. However, in routine clinical applications, there has been paucity in accurate quantitative methods for LDL-C. The calculation method widely used in clinical laboratories is based on a simple formula (Friedewald) that was introduced nearly fifty years ago. Since the 1990s, manufacturers have successively produced and promoted the method of direct measurement of LDL-C on selective enzymatic reactions. However, both approaches have significant biases in hyperlipidemic and hypolipidemic populations.
In the past decade, two innovative methods have emerged and gradually improved. The Martin/Hopkins method, first published in 2013, uses ultracentrifugation measurements as the reference method to obtain LDL-C values based on the corresponding values of total cholesterol, non-HDL cholesterol, and triglycerides by looking up a table [1]. In 2022 the Martin algorithm was further expanded to cover triglyceride levels up to 800 mg/dL [2]. The Sampson formula published in 2021 uses Beta quantification as the reference method and reports a multivariate mathematical formula to calculate LDL-C, which also covers triglyceride levels up to 800 mg/dL [3]. This formula is named after the front-line technician and can be easily applied in a clinical information system.
Professor Jing Cao from the University of Texas Southwestern Medical Center and collaborators reported that in a multiethnic population of more than 6,000 people, these two innovative methods more accurately predicted disease risk over a ten-year period, successfully avoiding misjudgment that leads to patients missing the opportunity of early prevention and treatment. Data from this study were published in Atherosclerosis, the official journal of the European Society of Atherosclerosis, and the International Society of Atherosclerosis [4].
In this year's JAMA Open Network journal, Martin's group compared LDL-C calculated at triglyceride levels of 400 to 799 mg/dL using the traditional Friedewald method, the extended Martin/Hopkins and Sampson methods [2]. In this study of more than 10,000 patients, the extended Martin/Hopkins and Sampson methods provided greater accuracy than the Friedewald method in all guideline classes of LDL-C from <40 to ≥190 mg/dL, and less underestimation of LDL-C.
Professor Jing Cao recently participated in the development of guidelines for the measurement of blood lipids in clinical laboratories initiated by the American Association of Clinical Chemistry Academy. Based on the excellent performance of these two innovative LDL-C calculation methods in accuracy and disease risk prediction, the new guidelines will recommend that the traditional Friedewald method be replaced by new calculation methods.
在针对动脉硬化型心血管疾病风险评估，预防，以及疗效观察的指南中，低密度脂蛋白胆固醇 (LDL-C) 一直是作为一项关键指标。然而在日常临床应用中，低密度脂蛋白胆固醇的检测一直缺少精确的定量方法。广泛使用于临床实验室的间接计算方法是基于一个近五十年前问世的简单公式 (Friedewald)。从上世纪九十年代开始，陆续有试剂厂家生产并推广通过选择性酶反应直接测量低密度脂蛋白胆固醇的方法。然而这两类方法在高血脂以及低血脂人群中都有着严重的偏差。
在过去的十年中，有两种创新的计算方法陆续面世并逐渐完善。Martin/Hopkins算法首次发表于2013年，是以超速离心测量为参考方法，通过查找表格，根据相应的总胆固醇，非高密度脂蛋白胆固醇和甘油三酯的数值得出低密度脂蛋白胆固醇数值 [1]。2022年Martin算法进一步扩大范围到覆盖高至800mg/dL甘油三酯水平 [2]。发表于2021年的Sampson公式是以Beta定量为参考方法，以多元数学公式计算出低密度脂蛋白胆固醇数值，同样可以覆盖高至800mg/dL甘油三酯水平 [3]。这项成果是以一线的技术员来命名，也能够非常方便地应用在临床信息系统内。
来自德克萨斯大学西南医学中心的曹静教授和合作者们报导了在超过6000人的多种族人群中，这两种创新的计算方法更加精准地预测了十年内的疾病风险，成功地避免了因为误判而使病人错失早期防治的机会。此项研究的数据发表在欧洲动脉硬化协会和国际动脉硬化协会的会员期刊，Atherosclerosis [4]。
在今年的JAMA Open Network期刊上，Martin课题组比较了传统的 Friedewald方法、扩展版的 Martin/Hopkins 和 Sampson 方法 在400 至 799 mg/dL 的甘油三酯水平下测量的 LDL-C [2]。在这项超过一万名患者的研究中，在从 <40 到 ≥190 mg/dL 的所有个体指南 LDL-C 等级中，扩展版Martin/Hopkins 和 Sampson 方法提供了比Friedewald方法更高的准确性，以及 更少的对低密度脂蛋白胆固醇的低估。
曹静教授近期参与了美国临床化学学院针对临床检验中血脂测量的指南撰写，根据这两种创新低密度脂蛋白胆固醇计算方法在准确性和临床风险预测中的优良表现，新的指南将会推荐由新型计算方法替代传统的Friedewald方法。
References
1. Martin, S.S., et al., Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA, 2013. 310(19): p. 2061-8.
2. Sajja, A., et al., Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels. JAMA Network Open, 2022. 4(10).
3. Sampson, M., et al., A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia. JAMA Cardiol, 2020. 5(5): p. 540-548.
4. Cao, J., et al., Performance of novel low-density lipoprotein-cholesterol calculation methods in predicting clinical and subclinical atherosclerotic cardiovascular disease risk: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis, 2021. 327.
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