Lipid Biomarkers: LDL Cholesterol

Optimal Takeaways

Low-density lipoproteins carry the cholesterol left over after triglycerides are cleaved from very low-density lipoproteins. If LDL particles are small, dense, and prone to oxidation, they can contribute to atherosclerosis and cardiovascular disease. LDL levels may vary due to genetic factors, and size can also vary and be smaller, denser, and more atherogenic, or larger, less dense, and less atherogenic. Low levels of LDL-C can increase the risk of all-cause mortality and intracerebral hemorrhage.

Standard Range: 1 - 100 mg/dL (0 - 2.59 mmol/L)

The ODX Range: 80 – 99.99 mg/dL (2.07 - 2.59 mmol/L)

Low LDL-C is associated with an increased risk of all-cause mortality (Penson 2018, Ravnskov 2016), intracerebral hemorrhage (Ma 2019), elevated liver transaminases (Jiang 2014), and malnutrition (Zhang 2017).

High LDL-C is associated with an increased risk for atherosclerosis and cardiovascular disease, especially when oxidized (Fernandez-Friera 2017). Higher LDL-C levels are also associated with vitamin D insufficiency (Lupton 2016). An LDL-C above 160 mg/dL (4.1 mmol/L) is associated with primary hypercholesterolemia (Arnett 2019).

Overview

Low-density lipoprotein (LDL) is a lipoprotein carrier produced mainly in the liver though some can also be made in the intestines (Pagana 2021). LDL transports cholesterol and other compounds through the blood and delivers them to tissues throughout the body. The LDL-C level that is available on blood chemistry reports may be measured directly or calculated. However, calculations are inaccurate if triglycerides are significantly elevated, i.e., above 300 mg/dL (3.36 mmol/L) (Millan 2009).

Although high LDL-C was initially believed to be the causative factor behind CVD, more advanced research reveals that several other factors contribute, including inflammation, oxidation, and inadequate HDL. Very low levels of LDL-C may increase the risk of disease and all-cause mortality.

Data review of 6136 high-risk individuals found that all-cause mortality was significantly increased when LDL-C was below 70 mg/dL, and hs-CRP was at least 2 mg/L. The lowest risk of stroke, CHD, and CHD mortality was in the group with LDL-C of 70 mg/dL (1.8 mmol/L) or above and hs-CRP below 2 mg/L. Researchers concluded that an LDL-C between 70 and 200 mg/dL (1.8-5.2 mmol/L) was protective and reduced the risk of all-cause mortality, even in those at high risk for CVD (Penson 2018). The inverse association between LDL-C and all-cause mortality was also confirmed in a systematic review of 19 studies comprising 68,094 subjects who were 60 years or older (Ravnskov 2016).

An LDL cholesterol below 70 mg/dL (1.8 mmol/L) was also associated with elevated liver enzymes in a review of NHANES data. Compared to the reference group having an LDL-C between 71-100 mg/dL (1.84-2.59 mmol/L), an LDL-C below 40 mg/dL (1.04 mmol/L) was associated with a 4.2-fold increase of elevated liver transaminases, while 41-70 mg/dL (1.06-1.8 mmol/L) was associated with a 1.6-fold increased risk (Jiang 2014).

An LDL-C below 70 mg/dL (1.8 mmol/L) was significantly associated with intracerebral hemorrhage (ICH) in a prospective study of 96,043 subjects. The association disappeared when LDL-C was 70 mg/dL or above. Researchers note that low total cholesterol of 188 mg/dL (4.87 mmol/L) or below was also associated with a significantly increased risk of ICH in this study (Ma 2019). Researchers suggest susceptibility to ICH may be due to RBC fragility when erythrocyte membrane cholesterol is too low.

A retrospective review of 868 hospitalized patient records found fewer CVD events occurred when the mean LDL-C was above 100 mg/dL (2.59 mmol/L) versus a mean LDL-C of less than 70 mg/dL (1.8 mmol/L). This observation was attributed to the larger LDL size in the higher LDL-C group (Wongcharoen 2017). The risks of low LDL-C should be recognized, as reducing LDL-C below 70 mg/dL is a common goal of statin therapy.

Assessment of LDL-C alone does not adequately assess cardiovascular risk or mortality. Researchers suggest that other lipid parameters must be considered when evaluating CVD risk. These include low HDL-C and elevated triglyceride:HDL-C ratio. In one prospective study of 51,462 individuals, all-cause mortality was positively associated with TG:HDL-C but was inversely associated with LDL-C, HDL-C, and total cholesterol, i.e., higher mortality with lower LDL-C (Orozco-Beltran 2017).

Oxidative stress is another factor that must be considered when evaluating cardiometabolic risk. Both the LDL carrier (Linton 2019) and cholesterol itself can become oxidized due to excess oxidative stress or insufficient antioxidant activity, resulting in an increased risk of atherosclerosis and cardiovascular disease (Weigel 2019).

Smaller, denser LDL particles (sdLDL) are more prone to oxidation and are especially atherogenic (Ivanova 2017). Fortunately, simple dietary changes such as increased consumption of high-antioxidant plant-based foods (e.g., berries and nuts) and omega-3 fatty acids have been associated with reduced sdLDL and oxidized LDL (Talebi 2020). A small study also found that coffee consumption also reduced the oxidation of LDL, possibly due to its phenolic content (Natella 2007).

Data review of a subset of 1,779 subjects in the PESA study found that the most extensive atherosclerosis was seen in those with a significantly higher oxidized LDL cholesterol: 50.3 mg/dL (1.3 mmol/L) versus 44.8 mg/dL (1.16 mmol/L) in those with no atherosclerosis. The level of LDL-C associated with the most extensive atherosclerosis was 132.4 mg/dL (3.43 mmol/L) versus 117 mg/dL (3.03 mmol/L) with no atherosclerosis. Mean fasting glucose was also higher in those with the most extensive atherosclerosis at 91 mg/dL (5.05 mmol/L) versus 86 mg/dL (4.77 mmol/L) with no atherosclerosis (Fernandez-Friera 2017).

Considering that LDL-C alone may not reflect health risks, consideration of HDL-C, non-HDL-C, triglycerides, lipoprotein subfractionation (particle size, density, and number), and oxidation should be incorporated into a comprehensive assessment.

References

Fernandez-Friera, Leticia et al. “Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.” Journal of the American College of Cardiology vol. 70,24 (2017): 2979-2991. doi:10.1016/j.jacc.2017.10.024

Ivanova, Ekaterina A et al. “Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases.” Oxidative medicine and cellular longevity vol. 2017 (2017): 1273042. doi:10.1155/2017/1273042

Jiang, Zhenghui Gordon et al. “Low LDL-C and high HDL-C levels are associated with elevated serum transaminases amongst adults in the United States: a cross-sectional study.” PloS one vol. 9,1 e85366. 15 Jan. 2014, doi:10.1371/journal.pone.0085366

Linton, MacRae F, et al. “The Role of Lipids and Lipoproteins in Atherosclerosis.” Endotext, edited by Kenneth R Feingold et. al., MDText.com, Inc., 3 January 2019.

Lupton, Joshua R et al. “Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study.” Journal of clinical lipidology vol. 10,1 (2016): 72-81.e1. doi:10.1016/j.jacl.2015.09.006

Ma, Chaoran et al. “Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study.” Neurology vol. 93,5 (2019): e445-e457. doi:10.1212/WNL.0000000000007853

Marz, Winfried et al. “HDL cholesterol: reappraisal of its clinical relevance.” Clinical research in cardiology : official journal of the German Cardiac Society vol. 106,9 (2017): 663-675. doi:10.1007/s00392-017-1106-1

Millan, Jesus et al. “Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention.” Vascular health and risk management vol. 5 (2009): 757-65.      

Natella, Fausta et al. “Coffee drinking induces incorporation of phenolic acids into LDL and increases the resistance of LDL to ex vivo oxidation in humans.” The American journal of clinical nutrition vol. 86,3 (2007): 604-9. doi:10.1093/ajcn/86.3.604

Orozco-Beltran, Domingo et al. “Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.” PloS one vol. 12,10 e0186196. 18 Oct. 2017, doi:10.1371/journal.pone.0186196 Correction

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Penson, Peter E et al. “Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study.” European heart journal vol. 39,40 (2018): 3641-3653. doi:10.1093/eurheartj/ehy533

Ravnskov, Uffe et al. “Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review.” BMJ open vol. 6,6 e010401. 12 Jun. 2016, doi:10.1136/bmjopen-2015-010401

Talebi, Sepide et al. “The beneficial effects of nutraceuticals and natural products on small dense LDL levels, LDL particle number and LDL particle size: a clinical review.” Lipids in health and disease vol. 19,1 66. 11 Apr. 2020, doi:10.1186/s12944-020-01250-6

Weigel, Thaddeus K et al. “Oxidized cholesterol species as signaling molecules in the brain: diabetes and Alzheimer's disease.” Neuronal signaling vol. 3,4 (2019): NS20190068. doi:10.1042/NS20190068

Wongcharoen, Wanwarang et al. “Is non-HDL-cholesterol a better predictor of long-term outcome in patients after acute myocardial infarction compared to LDL-cholesterol? : a retrospective study.” BMC cardiovascular disorders vol. 17,1 10. 5 Jan. 2017, doi:10.1186/s12872-016-0450-9