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June 12, 2023

Whose Cholesterol is it Anyway? Updating the Update on Total Cholesterol

In this post, the ODX Research team evaluates cholesterol’s role in human metabolism and proposes a new optimal range for Total Cholesterol.

Cholesterol is much more than just a popular topic. It is a vital compound required for numerous functions…which is why it can be produced by just about every cell in the body. It is a structural and functional element of cell membranes, a primary lipid in the brain and central nervous system, and a precursor to all steroid hormones, vitamin D, and bile salts (Huff 2020, Schade 2020).              

Most importantly, cholesterol is essential to nerve transmission and neural function; cell membrane fluidity and permeability; growth and development; digestion and absorption; vitamin D synthesis; stress response; blood pressure; and fluid and salt balance.

Cholesterol and Disease Risk

Total cholesterol levels have traditionally been considered a risk factor for cardiovascular disease (CVD). However, conventional research reveals that as a standalone biomarker, total cholesterol doesn’t provide enough information about cardiovascular risk.

We also need to know more about the number, size, and characteristics of cholesterol lipoprotein carriers (i.e., VLDL, IDL, LDL, and HDL). We must also consider whether cholesterol has become oxidized, making it much more atherogenic, and whether elevated serum cholesterol is due to familial hypercholesterolemia, a genetic disorder that fails to regulate cholesterol production (Ivanova 2017, Gao 2018).        

We also know that it’s essential to evaluate downstream metabolites of cholesterol, including glucocorticoids, mineralocorticoids, sex hormones, and vitamin D, to understand why cholesterol levels may be increased or decreased. Disruption of cholesterol metabolism may affect the numerous functions performed by its metabolism.

Assessing cardiovascular risk using only total cholesterol does not identify known CVD risk factors, including inflammation, oxidative stress, an unhealthy processed diet, nutrient insufficiencies, excess toxin exposure, and blood glucose dysregulation. A cardiovascular risk assessment should include evaluating these factors and additional biomarkers such as hs-CRP, fibrinogen, homocysteine, lipoprotein subfractionation, triglycerides, fasting glucose, and fasting insulin for starters.

Total Cholesterol Levels: Highs and Lows

Highly elevated total cholesterol above 350 mg/dL (9 mmol/L) is usually associated with a genetic disorder called familial hypercholesterolemia. This disorder is also associated with highly elevated LDL and non-HDL cholesterol (Pejic 2013).  

In the absence of familial hypercholesterolemia, total cholesterol above 200 mg/dL (5.2 mmol/L) should be investigated further in those at increased risk of cardiovascular disease, inflammation, and oxidative stress. Excess cholesterol can also build up and contribute to liver dysfunction if not appropriately processed (Püschel 2019).    

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 cholesterol may be well tolerated in some individuals.

Low total cholesterol may indicate malnutrition and an increased risk of psychological disorders, neurodegenerative disease, and all-cause mortality, especially if levels drop below 160 mg/dL (4.14 mmol/L) (Nago 2011, Schatz 2001, Wu 2019). Total cholesterol below 145 mg/dL (3.78 mmol/L) is associated with an increased risk of depression and suicidal ideation (Messaoud 2017, Tomson-Johanson 2018).            

Healthy middle-aged individuals with total cholesterol 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). In this group of 12,334 individuals, levels 239 mg/dL (6.2 mmol/L) or above were not associated with an increased risk of death (Nago 2011).

Cholesterol and Hormone Balance

Since cholesterol is the precursor to glucocorticoids, mineralocorticoids, sex hormones, and vitamin D, a disruption in its metabolism can affect the balance of downstream metabolites. For example, statin-induced inhibition of cholesterol synthesis was associated with declines in serum testosterone (Baspınar 2016, Dobs 2000). Statins can also deplete CoQ10 by up to 40%, which is especially detrimental in those with heart failure or diabetes, or who are elderly (Zozina 2018).        

The thyroid gland regulates cholesterol metabolism, and elevated cholesterol may be associated with hypothyroidism. Administration of thyroid hormone decreased high cholesterol, initially above 290 mg/dL (7.5 mmol/L), in those with TSH above optimal who had elevated thyroid autoantibodies (Michalopoulou 1998).  

Cholesterol Caveats

In those with a low risk of CVD and oxidative stress, total cholesterol up to 249 mg/dL (6.5 mmol/L) may be acceptable, depending on lipoprotein breakdown and characteristics (Yi 2019).

Higher levels of total cholesterol in older individuals may be associated with reduced risk of mortality, in some cases with total cholesterol between 211-329 mg/dL (5.46-8.52 mmol/L), except those with an HDL cholesterol below 43 mg/dL (1.11 mmol/L), which emerged as a significant independent risk factor for CVD and higher mortality (Orozco-Beltran 2017).

The Progression of Early Subclinical Atherosclerosis (PESA) study found that individuals with no atherosclerosis had a mean total cholesterol of 187 mg/dL (4.84 mmol/L). In comparison, those with the most extensive atherosclerosis had mean total cholesterol of 201.1 mg/dL (5.2 mmol/L) accompanied by 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).

Fasting total cholesterol 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).

Total cholesterol above 180 mg/dL (4.66 mmol/L) may be protective against Parkinson’s disease (Rozani 2018, Huang 2011).

Optimal Takeaways

As you can see, cholesterol is an indispensable compound produced in the body for several reasons. It is essential to cell membrane integrity, brain and nervous system function, and hormone and vitamin D synthesis.

  • Total cholesterol levels above optimal should be evaluated on an individual basis, including a full assessment of genetic hypercholesterolemia (if 350 mg/dL and above); cardiovascular risk; lipoprotein breakdown, particle size, and number; thyroid function; hormone balance; and neurodegenerative risk.
  • Levels below optimal should prompt an evaluation of nutrition status, neurological and mood impacts, and risk of heart failure and stroke.
  • A starting point for an optimal total cholesterol range would be 160-199 mg/dL (4.14-5.15 mmol/L). Levels below that should be investigated further for possible association with malnutrition or increased neurodegenerative risk.
  • Levels above that optimal range should be further investigated for association with cardiovascular risk. A higher serum cholesterol level may be acceptable and even protective if the CVD risk is low.

Want to Learn More?

CLICK HERE to learn more about Total Cholesterol, health consequences, the ODX ranges, etc.

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Tag(s): Biomarkers

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