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Welcome to episode 2 of "Optimal - The Podcast". In this episode of Optimal, we are going to talk about Cholesterol. Yes. That very basic building block of human biochemistry and physiology that everyone seems to have such strong opinions about.
In the first part of the Podcast, we’re going to be talking about Cholesterol the molecule and at the end of the podcast, we’ll dive into Cholesterol the biomarker and look at ranges, clinical implications, research, etc.
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Cholesterol is an important sterol lipid made in the body; it is also found in animal-based foods. It's synthesized from acetyl-CoA which can be obtained from carbohydrate, fat, or protein.[i] [ii] An important player in its synthesis is an enzyme called HMG-CoA reductase. We will be talking about this enzyme a little bit later. Cholesterol is produced by every cell in the body though most production takes place in the liver. It is found in every cell membrane and is the most abundant lipid in the brain.[iii] Cholesterol is found in abundance in the central and peripheral nervous systems, especially the myelin sheath.[iv] It is rate limiting for myelination in the central nervous system. [v]
It is the precursor to:
Vitamin D: Cholesterol in the form of 7-dehydrocholesterol is the precursor to vitamin D synthesis in the skin when exposed to UV light/sunlight.
Bile salts: Cholesterol is needed for production of bile salts which facilitate digestion of fat and absorption of fat-soluble vitamins (ADEK).
Cholesterol possesses antioxidant activity:
The antioxidant functions of cholesterol were recognized early on and discussed in the 1970s. Cholesterol can intercept oxidants in a protective role though oxysterols are produced which then must be eliminated via bile and feces. Depletion of cholesterol will contribute to increased oxidative stress and, ironically, disrupt cell membrane function.[vii] [viii]
Unfortunately, the vital functions and benefits of cholesterol have been overshadowed by the assumption that cholesterol itself is a “bad thing.”
Despite assumptions to the contrary, dietary cholesterol does itself does not contribute to elevated serum cholesterol or cardiovascular disease (though oxidized cholesterol is a cuprit). Most often dietary cholesterol will have an insignificant effect on blood cholesterol levels as it triggers a feedback loop (via HMG Co-A reductase) that reduces endogenous production. Also, a relative rise in blood cholesterol following dietary intake reflects a fairly balanced rise in both LDL and HDL cholesterol. Interestingly, a meta-analysis revealed that a pronounced increase in HDL cholesterol occurred with dietary cholesterol intake of 650-900 mg/day.[ix]
Dietary cholesterol promotes the repair of demyelinated lesions in the adult brain. In animal models of multiple sclerosis/demyelination, dietary cholesterol restored cholesterol levels depleted by acute disease and enhanced remyelination and diminished axon damage.[x] Even the much maligned egg has been pardoned as well-designed studies indicate that egg intake did not negatively impact blood lipids for most individuals. In some cases, eggs shifted LDL to the preferred larger “fluffier” LDL particles and did not appear to promote oxidized LDL cholesterol. Egg intake may be associated with cardiovascular disease in diabetics, but that association may be due to production of microbial production of TMAO from the phosphatidylcholine in the egg yolk.[xi] Those with familial hypercholesterolemia must be assessed and treated accordingly.
Current research has shifted its focus away from cholesterol and toward systemic inflammation which is becoming one of the most likely of the usual suspects when it comes to cardiovascular disease.[xii] But we’ll save that hot topic for another day.
Complete a full assessment of cardiovascular risk factors, not just total cholesterol, including[xxi]
Complete full assessment of serum lipids including total, LDL and particle size/number, HDL and particle size/number, non-HDL, VLDL, triglycerides, ApoA-1, ApoB, Lp(a), etc.
Assess for familial hypercholesterolemia (FH)[xxiii]
Assess antioxidant potential and oxidative stress risk (start with diet & environment)
Assess downstream metabolites (steroid hormones, vitamin D, etc.)
Assess additional cardiovascular biomarkers e.g.
Alright, let’s get back to our topic of the month and that’s Cholesterol and I want to take the last 10 – 15 minutes looking at Cholesterol biomarkers.
Because cholesterol is basically lipophilic, it must be transported in the blood inside lipoprotein carriers including VLDL, LDL, and HDL which can be easily measured.[xxiv] And these form the traditional cholesterol biomarkers that make up the standard Lipid Panel.
Let’s start with the one that people probably have the most opinions about and that’s total cholesterol. Total cholesterol levels are just one piece of the cardiovascular disease puzzle and must be assessed further. A low cholesterol level may reflect malnutrition or severe oxidative stress. Total cholesterol does not provide enough information about CVD risk for those who do not have familial hypercholesterolemia.
Cholesterol levels and ranges
Let’s take a look at Standard total cholesterol recommendations for adults:
2013 American College of Cardiologists/American Heart Association Guidelines
Therapeutic goals for total cholesterol ranged from 220 mg/dL to below 200 mg/dl (5.69-5.17 mmol/L).[xxv]
Interestingly, in the executive summary of 2019 Updated ACC/AHA guidelines they don’t discuss Total Cholesterol but instead emphasize lifestyle and dietary changes. They focus less on total cholesterol levels but do provide guidance for LDL and non-HDL[xxvi] Their recommendations for a cut-off for a diagnosis of Primary hypercholesterolemia:
National Lipid Association Recommendations
Borderline high: 200-239 mg/dL (5.17-6.18 mmol/L)
High: 240 mg/dL (6.2 mmol/L) or above [xxviii]
US National Library of Medicine: “Healthy” levels of total cholesterol
Men and women age 20 or older: Total Cholesterol 125 to 200 mg/dL [xxix]
Interestingly, a low cholesterol below 160 mg/dL and high cholesterol >240 mg/dL is associated with severe acute pancreatitis[xxx]
So that’s the standard or “normal” range . And because this podcast and the work of Optimal DX is “Don’t settle for normal, strive for optimal” I do want to take a quick look at Optimal ranges for total cholesterol
A retrospective study that appeared in the journal “Lipid Health Disorders” in January 2019 looked at 1754 healthcare workers at low risk of cardiovascular disease examined the screening value of total cholesterol levels.
In view of the vital importance of cholesterol to cellular metabolism and its vulnerability to oxidation and inflammation, a reasonable and optimal total cholesterol level would be 160 - 200 mg/dl
Additional assessment in those with cardiovascular disease or at risk for cardiovascular disease should be considered.
So, Beth, it looks as if Total Cholesterol as a biomarker is controversial, but really its importance is somewhat overblown and the more important players on the lipid panel are LDL, HDL and Non-HDL. Can you take us on a quick journey on those?
A prospective cohort study revealed that subclinical atherosclerosis was present in half of the 1,779 participants who had no major cardiovascular risk factors. The most extensive atherosclerosis was found in those mean levels of total cholesterol of 201 mg/dL, LDL-C of 132 mg/dL, and oxidized LDL-C of 50 mg/dL. Atherosclerosis was also associated with hemoglobin A1C of greater than 5.7%.[xxxii]
HDL cholesterol (reverse cholesterol transport)
HDL is an important factor in reverse cholesterol transport, taking cholesterol, including oxidized cholesterol, from the cells back to the liver for processing. Optimal levels range from 55-70 mg/dL, however elevated HDL-C of 90 mg/dL or greater have been associated with an increased risk of cardiovascular events and mortality.[xxxiii]
Although it is traditionally accepted that increased HDL represents decreased risk of coronary artery disease independent of LDL levels,[xxxiv] additional research reveals that extremely high HDL levels are associated with increased risk of cardiovascular events and mortality.[xxxv]
Japanese cohort: the highest level of HDL-C (≥ 90 mg/dL) for both men and women was associated with increased risk of mortality from atherosclerotic CVD, CHD, and ischemic stroke
Danish cohort: In fully adjusted models for men, baseline HDL-C at 73 mg/dL (95% CI, 42-77 mg/dL) was associated with the lowest mortality. In fully adjusted models for women, the lowest mortality was seen at a baseline HDL-C of 93mg/dL (95% CI, 66-239 mg/dL).
VLDL is a lipoprotein that mainly carries triglycerides with some cholesterol. Once triglycerides are dropped off, VLDL becomes IDL and finally LDL. It’s important to assess VLDL size and number.
Non-HDL cholesterol is potentially atherogenic, representing LDL, IDL, VLDL, and lipoprotein(a). It is significantly associated with increased incidence of major adverse cardiovascular events (MACEs). Post-acute MI patients with non-HDL of greater than 130 mg/dL had three times the risk of long-term MACEs than those with non-HDL of less than 100 mg/dL.
Surprisingly, a mean LDL-C of greater than 100 mg/dL was associated with fewer cardiovascular events than a mean LDL-C of less than 70 mg/dL (1.8 mmol/L) (a common goal of statin therapy[xxxvi]), an observation attributed to larger LDL size in the higher LDL-C group[xxxvii]
I want to finish up by looking at something that Beth and I have been reporting on for a while and that’s the value of ratios and there are a few very important ratios that appear on the standard lipid panel: Total Cholesterol:HDL, LDL:HDL, and ApoB:Apo A1.
Assessing the ratios of total cholesterol/HD, LDL/HDL, and ApoB/ApoA-1 provide greater predictive value in terms of cardiovascular risk than assessing either value alone. [xxxviii]
Total cholesterol:HDL-C (“atherogenic or Castelli index)
[i] Mahan, L. Kathleen; Raymond, Janice L. Krause's Food & the Nutrition Care Process - E-Book (Krause's Food & Nutrition Therapy) (p. 427). Elsevier Health Sciences. Kindle Edition.
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