Lipid Biomarkers: Total Cholesterol

Optimal Takeaways

Cholesterol is a vital compound produced in the body and used to make cell membranes, steroid hormones, vitamin D, and bile acids. It is essential to the synthesis of the protective myelin sheath around nerve cells and is the most abundant lipid in the brain. If cholesterol becomes oxidized and embedded into blood vessels, it can contribute to atherosclerosis and CVD. Low cholesterol is associated with malnutrition, depression, aggressive behavior, and neurodegenerative disease. Higher cholesterol levels may be associated with genetic factors, hypothyroidism, and CVD if associated with other risk factors.

Standard Range: 125 - 199 mg/dL (3.23 - 5.15 mmol/L)

The ODX Range: 160 - 199 mg/dL (4.14 – 5.15 mmol/L)  

Low total cholesterol is seen with malnutrition, malabsorption, stress, sepsis, liver disease, acute myocardial infarction, hemolytic anemia, pernicious anemia, and certain drugs, including statins, captopril, androgens, MAO inhibitors, nitrates, niacin, allopurinol, colchicine, liothyronine, erythromycin, and bile salt-binding agents (Pagana 2021).

Lower cholesterol can also be seen with chronic infection or subclinical disease (Cabrera 2012), hyperthyroidism (Rizos 2011, Kotwal 2020, Pagana 2021), depression, aggression, suicidal thoughts, disrupted hormone metabolism, and neurodegenerative diseases (Zubeldia-Brenner 2016), including Parkinson’s disease (Jin 2019).

High total cholesterol is seen with familial hyperlipidemia, uncontrolled diabetes, nephrotic syndrome, hypertension, atherosclerosis, biliary cirrhosis, hyperlipoproteinemia, pregnancy, oophorectomy (Pagana 2021), and hypothyroidism (Jung 2017, Biondi 2008, Pagana 2021). Elevated total cholesterol (and triglycerides) is also associated with persistent organic pollutants (e.g., PCBs, DDT, and fat-soluble pesticides (Aminov 2013).

Overview 

Cholesterol is a vital steroid-based lipid with a wide range of functions. It is produced in the body from acetyl-CoA obtained from carbohydrates, fat, or protein and is also found in animal-based foods (Craig 2019).

Cholesterol is vital to health as it is a functional component of cell membranes, the rate-limiting compound for myelinization, the most abundant lipid in the brain, and the precursor to bile acids and steroid hormones, including glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), sex hormones (e.g., pregnenolone, progesterone, estrogen, testosterone), and vitamin D. Cholesterol facilitates cell signaling, nerve conduction, and intracellular transport (Schade 2020, Huff 2020, Hu 2010, Whitney 2008, Mahan 2016, Agranoff 1999, Snipes 1997, Tsoupras 2018, Berghoff 2017).

Although all cells can produce cholesterol, it is primarily produced in the liver from acetyl-CoA via the action of HMG CoA reductase. Inhibition of the HMG-CoA reductase enzyme will reduce the production of cholesterol, CoQ10, and squalene (Zozina 2018).

Because cholesterol is lipophilic, it must be carried in the blood by lipoproteins, compounds with varying amounts of lipids and protein. Total cholesterol (TC) measures the amount carried by all lipoproteins, i.e., VLDL, IDL, LDL, and HDL. Both VLDL and IDL contain remnant cholesterol and are considered the most atherogenic because they are more inflammatory and can be taken up by endothelial macrophages without being oxidized. LDL is also atherogenic, especially when small, dense, and oxidized, while HDL can be protective as it scavenges cholesterol through reverse cholesterol transport (Schade 2020).

Elevated cholesterol may be due to familial hypercholesterolemia. A TC above 350 mg/dL (9 mmol/L) or an LDL-C above 190 mg/dL (4.9 mmol/L) may be indicative of this genetic disorder (Pejic 2014). A fasting TC above 230 mg/dL (6 mmol/L) may be reflective of higher LDL-C of at least 160 mg/dL (4.1 mmol/L) and/or non-HDL cholesterol of at least 190 mg/dL (4.9 mmol/L), warranting further evaluation (Nantsupawat 2019).

In a meta-analysis of 40 studies, dietary cholesterol was not significantly associated with coronary artery disease or stroke. Dietary cholesterol did increase total, HDL, and LDL cholesterol. However, the association with LDL was not significant when cholesterol intake exceeded 900 mg per day, possibly due to the feedback mechanism that decreases endogenous cholesterol synthesis (Berger 2015).

As the thyroid gland regulates cholesterol and lipid metabolism, cholesterol levels are influenced by thyroid function. Thyroid dysfunction can be reflected in total cholesterol levels. Hypothyroidism is associated with elevated cholesterol (Jung 2017). Total cholesterol, LDL cholesterol, and non-HDL cholesterol have a positive statistical association with TSH, increasing consistently as TSH increases, especially in individuals with thyroid autoantibodies (Biondi 2008). In those with autoantibodies, TC above 290 mg/dL was reduced with the administration of thyroxine (Michalopoulou 1998). Hyperthyroidism is associated with low cholesterol levels (Rizos 2011). According to a 2020 systematic review and meta-analysis, overt hyperthyroidism is associated with a mean low cholesterol of 158.7 mg/dL (4.11 mmol/L) (Kotwal 2020).

The relationship between total cholesterol and cardiovascular risk has become surprisingly unclear. Early research associated TC above 200 mg/dL (5.18 mmol/L) with graded increases in CHD, CVD, and all-cause mortality in three long-term prospective studies of 11,017 men aged 18 to 39. Researchers noted a 2.1-3.63 increased relative risk for cardiovascular mortality in those with a TC above 200 mg/dL (5.18 mmol/L) versus a level below 200 mg/dL (Stamler 2000).

However, higher levels of TC in older individuals may be associated with a reduced mortality risk. A large prospective study examined 51,462 men and women at high risk for CVD with dyslipidemia, hypertension, or diabetes but no CVD diagnosis or event at baseline. The mean age of participants was 62.6 years (Orozco-Beltran 2017). Higher total cholesterol levels were associated with lower mortality risk in this study. Total cholesterol of 238-329 mg/dL (6.16-8.52 mmol/L) was associated with the lowest mortality rate, while a range of 211-237 mg/dL (5.46-6.14 mmol/L) was associated with the lowest CVD hospitalization. However, the highest rates of all-cause mortality and CVD hospitalization occurred in the group with lower total cholesterol in the range of 118-183 mg/dL (3.06-4.74 mmol/L). HDL-C emerged as a significant and independent risk factor for CVD, with a low HDL-C in the range of 38-43 mg/dL (0.98-1.11 mmol/L) being associated with the highest mortality.

Total cholesterol levels were evaluated in The Korean Metabolic Risk Factor (KOMERIT), a study of 12.8 million adults. Results indicated that the association of TC with mortality followed a U-shaped curve. Researchers concluded that those without ischemic heart disease had the lowest mortality rates associated with TC of 210-249 mg/dL (5.4-6.5 mmol/L). Exceptions to this observation were 18–34-year-old males with the lowest mortality with TC of 180-219 mg/dL (4.7-5.7 mmol/L). In women, the lowest mortality was associated with a TC of 160-199 mg/dL (4.1-5.2 mmol/L) in ages 18-34 years; and 180-219 mg/dL (4.7-5.7 mmol/L) in ages 34-44 years (Yi 2019).

Data from 4,184 healthy individuals enrolled in the Progression of Early Subclinical Atherosclerosis (PESA) study found subclinical atherosclerosis (coronary artery calcification or plaque) in 50% of the study population despite them not being identified as high risk. Those with no atherosclerosis had a mean TC of 187 mg/dL (4.84 mmol/L), while those with the most extensive atherosclerosis had a mean TC of 201.1 mg/dL (5.2 mmol/L), as well as LDL-C above 132 mg/dL (3.42 mmol/L), and oxidized LDL-C above 50 mg/dL (1.3 mmol/L) (Fernandez-Friera 2017).

An observational study of 800 older adults aged 60-85 found no association between elevated TC and all-cause mortality. On the contrary, a TC above 200 mg/dL (5.18 mmol/L) was associated with lower mortality, while a level below 170 mg/dL (4.4 mmol/L) was associated with higher mortality (Cabrera 2012). Age may influence these observations, as the study did not include adults under 60.

A large prospective Norwegian study of 52,087 CVD-free individuals noted a U-shaped association between total cholesterol and ischemic heart disease. This pattern was most evident in women with the highest mortality rates from ischemic heart disease with TC at or above 270 mg/dL (7 mmol/L) or below 193 mg/dL (5 mmol/L). Lower cholesterol levels were not stratified in the study (Petursson 2012).

Low total cholesterol, particularly below 160 mg/dL (4.14 mmol/L), can be a sign of malnutrition and may be a risk factor for depression, aggressive and antisocial behavior, suicidal ideation, neurodegenerative disease, and hormone metabolism impairment (Zubeldia-Brenner 2016). A systematic review and meta-analysis of 111 studies comprising 52,911 older individuals found that a TC below 166 mg/dL (4.3 mmol/L) was associated with a significantly greater risk of malnutrition using the Subjective Global Assessment tool (Zhang 2017).

Cholesterol is the most abundant lipid in the brain, where it is produced locally and maintained mostly in unesterified form. Although the blood-brain barrier prevents circulating lipoprotein-bound cholesterol from entering the brain, low serum levels of total, VLDL, and LDL cholesterol, as well as triglycerides, were significantly lower in Parkinson’s disease, suggesting an important association (Jin 2019).

A cut-off below 160 mg/dL (4.14 mmol/L) for cholesterol is considered a risk factor for mortality (Fulks 2010). A prospective study of 12,334 healthy individuals 40-69 years old revealed that those with TC below 160 mg/dL had significantly greater mortality from heart failure, hemorrhagic stroke, and cancer compared to moderate total cholesterol levels of 160-200 mg/dL (4.14–5.2 mmol/L). Even at higher levels, total cholesterol of 239 mg/dL (6.2 mmol/L) or greater was not associated with an increased risk of death (Nago 2011).

A full biochemical cardiovascular assessment should go beyond total cholesterol and incorporate lipoprotein analysis and subfractionation via NMR or ION mobility technology. Further evaluation should include additional cardiovascular risk biomarkers, including hs-CRP, GlycA, fibrinogen, oxidized LDL, homocysteine, uric acid, and glucose regulation biomarkers.  

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