Lipid Biomarkers: HDL Cholesterol

Optimal Takeaways

High-density lipoprotein scavenges cholesterol from around the body and returns it to the liver for processing. It is mainly a beneficial lipoprotein but can become pathogenic if modified by inflammation, immune activity, and toxins, including pesticides.

Low HDL is associated with CVD, metabolic syndrome, inflammation, genetic factors, hyperthyroidism, and liver disease. High HDL may be related to genetic factors, excess exercise, and increased all-cause mortality. Very high or very low HDL should be evaluated alongside other cardiovascular and genetic risk factors.

Standard Range: 46 - 100 mg/dL (1.19 - 2.59 mmol/L)

The ODX Range: 55 – 93 mg/dL (1.42 – 2.41 mmol/L)

Low HDL-C is associated with cardiovascular risk (Orozco-Beltran 2017), metabolic syndrome, vascular dementia, Alzheimer’s risk (Cho 2022), liver disease, hypoproteinemia, nephrotic syndrome, malnutrition, hyperthyroidism, and familial low HDL (Pagana 2022).

Low HDL may also be associated with acute inflammation (Bardagiy 2019), chronic inflammation, and disruptions in triglyceride metabolism (Marz 2017). Low HDL-C is also associated with vitamin D insufficiency (Lupton 2016).

High HDL-C is associated with familial high HDL, lipoproteinemia, hypothyroidism, excess exercise (Pagana 2022), elevated liver enzymes (Jiang 2014), and increased all-cause mortality (Madsen 2017).

Overview

High-density lipoprotein (HDL) is the lipoprotein highest in protein. It acts as a “scavenger” that picks up cholesterol around the body, including from macrophages and atherosclerotic plaque. It brings it back to the liver in a process called reverse cholesterol transport or efflux (Lee 2021). Cholesterol carried by HDL is called HDL cholesterol (HDL-C); the amount of HDL-C in the core of an HDL particle varies and is higher in larger HDL particles (Wilkins 2019).

Low HDL cholesterol is currently considered a risk factor for CVD, while modestly higher levels are primarily protective. Levels above 60 mg/dL (1.55 mmol/L) may represent increased HDL2b, the cardioprotective form responsible for efficient reverse cholesterol transport (Pagana 2022).

One large study looked at 73,302 individuals at high risk for CVD due to dyslipidemia, hypertension, or diabetes, but no CVD diagnosis or event. Those with the highest mortality had an HDL-C of 27-43 mg/dL (0.7-1.11 mmol/L) and total cholesterol:HDL-C of 5.58.

Those with the lowest mortality had an HDL-C of 62-98 mg/dL (1.61-2.54 mmol/L) and a TC:HDL-C ratio of 2.96. Researchers conclude that low HDL-C is an independent risk factor for CVD and that TC:HDL-C ratio should also be considered. Unfortunately, the study did not look at other CVD risk factors such as hs-CRP, fibrinogen, homocysteine, oxidized LDL-C, or subfractionation of lipoprotein size and number (Orozco-Beltran 2017).

Analysis of the Framingham study suggests that LDL-C and triglycerides (TGs) should be considered when evaluating HDL-C. Cardiovascular risk increased by 30% when low HDL-C was coupled with LDL-C of 100 mg/dL (2.59 mmol/L) or higher and TG below 100 mg/dL (1.13 mmol/L). Risk increased by 60% when low HDL-C was present, with LDL-C and TG reaching 100 mg/dL or higher (Marz 2017).

Further literature review notes a U-shaped relationship between HDL-C and mortality; risk increases when HDL-C falls below 50 mg/dL (1.25 mmol/L). Beneficial increases in HDL-C may be achieved via a Mediterranean-style diet, physical activity, weight loss, smoking cessation, and moderate alcohol consumption. However, further benefit or improved prognosis was not seen with HDL-C greater than 60 mg/dL (1.5 mmol/) (Marz 2017).

It is becoming clear that exceptionally high HDL is not desirable. A review of data from two prospective population-based studies comprising 52,268 men and 64,240 women confirmed a U-shaped curve for all-cause mortality based on HDL-C levels. Researchers conclude that the lowest all-cause mortality observed was associated with a mean HDL-C of 73 mg/dL (1.86 mmol/L) in men and 93 mg/dL (2.41 mmol/L) in women. The highest mortality was observed with an HDL-C of 116 mg/dL (3.0 mmol/L) or higher in men and 135 mg/L (3.5 mmol/L) or higher in women (Madsen 2017).

A review of NHANES data found that an HDL-C above 100 mg/dL (2.59 mmol/L) was associated with a 3.2 increased risk of elevated liver enzymes when compared to a level of 61-80 mg/dL (1.58 mmol/L) (Jiang 2014).

Although increased or decreased circulating levels of HDL-C may be associated with variations in cardiovascular risk, the functionality of the HDL molecule itself will determine its cardioprotective benefits.

Acute inflammation can decrease HDL, and inflammatory molecules such as SAA can impair its vital antioxidant, anti-inflammatory, and reverse cholesterol transport functions (Bardagjy 2019). HDL can become pathologically altered by immune cell activity and inflammation and become atherogenic (Shah 2019). HDL can also lose its antioxidant capacity due to glycation (Cho 2022) or pesticide exposure (Ljunggren 2014).

References

Bardagjy, Allison S, and Francene M Steinberg. “Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.” Nutrients vol. 11,6 1231. 30 May. 2019, doi:10.3390/nu11061231

Cho, Kyung-Hyun. “The Current Status of Research on High-Density Lipoproteins (HDL): A Paradigm Shift from HDL Quantity to HDL Quality and HDL Functionality.” International journal of molecular sciences vol. 23,7 3967. 2 Apr. 2022, doi:10.3390/ijms23073967

de Miranda Teixeira, Raissa et al. “HDL Particle Size and Functionality Comparison between Patients with and without Confirmed Acute Myocardial Infarction.” Cardiology research and practice vol. 2019 3074602. 3 Mar. 2019, doi:10.1155/2019/3074602

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

Lee, Jane J et al. “Cholesterol Efflux Capacity and Its Association With Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis.” Frontiers in cardiovascular medicine vol. 8 774418. 13 Dec. 2021, doi:10.3389/fcvm.2021.774418

Ljunggren, Stefan A et al. “Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.” Environment international vol. 65 (2014): 93-9. doi:10.1016/j.envint.2013.12.017

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

Madsen, Christian M et al. “Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies.” European heart journal vol. 38,32 (2017): 2478-2486. doi:10.1093/eurheartj/ehx163

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.      

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. 16th ed., Mosby, 2022.

Shah, Prediman K, and Dalgisio Lecis. “Inflammation in atherosclerotic cardiovascular disease.” F1000Research vol. 8 F1000 Faculty Rev-1402. 9 Aug. 2019, doi:10.12688/f1000research.18901.1

Wilkins, John T, and Henrique S Seckler. “HDL modification: recent developments and their relevance to atherosclerotic cardiovascular disease.” Current opinion in lipidology vol. 30,1 (2019): 24-29. doi:10.1097/MOL.0000000000000571