The Problems with Cholesterol Testing

When it comes to health, cholesterol is a much discussed subject.  It is often given a negative connotation but cholesterol is not inherently bad.  In fact, this waxy substance is necessary for life and our bodies are able to make all they require for well-being.

Cholesterol is carried by the bloodstream throughout the body within particles called lipoproteins.  The main lipoproteins are;

LDL-cholesterol – often called “bad cholesterol” because it can build up in artery walls causing blockages

HDL-cholesterol – often called “good cholesterol” because it helps to carry cholesterol away from the arteries and out of the body

VLDL-cholesterol – particles carrying triglycerides (other fats that are derived from the food that we eat) and which are also associated with cardiovascular disease

The reason cholesterol levels are monitored is because of their relationship with the development of atherosclerotic cardiovascular disease (aka coronary artery disease), the build up of cholesterol and other substances within the inner walls of arteries which causes narrowing of the arteries and a reduction in the amount of blood feeding the heart and the brain (1,2).

 High LDL-cholesterol levels are now considered an undeniable cause of cardiovascular disease.  A 2017 comprehensive review of current clinical and genetic evidence regarding the association between LDL-cholesterol and damaged arteries concluded that “consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL-cholesterol causes atherosclerotic cardiovascular disease.” (3)  Consequently, many people looking to improve their future health undertake transformations in diet and lifestyle with the goal of reducing their cholesterol blood levels.

Unfortunately, depending on cholesterol level as the key measure of heart health can be a dicey matter.

When it comes to the health of your blood vessels;

• There are a great many variables playing into an individual’s blood cholesterol measurement.
• There are other means besides cholesterol levels available to help in assessing the health of your blood vessels.
• There are steps you can take to improve the health of your blood vessels that do not include taking a pill that can have adverse side effects.

This article, Cholesterol Concerns: Part One, will examine the circumstances that can confound a simple cholesterol test.

Cholesterol Concerns: Part Two investigates alternate methods of “looking” inside your cardiovascular system to see what is going on.  In addition, it offers solutions that can galvanize you into life-changing action.

 

Factors Affecting Normal Cholesterol Blood Levels for Individuals

Cholesterol blood levels vary widely among different people.  Genetics, age, gender, amount and type of exercise, dietary factors, time of year, and even the time of day that blood is drawn for a cholesterol test as well as the actual lab that processes the test all play a part in this situation.

 Note:  There are two different international units of measure for cholesterol blood levels.  Canada, along with the UK, some other European countries, Australia and South Africa use millimoles per liter (mmol/L).  The US, France, Egypt, Italy, India, Japan and most of South America use milligrams per deciliter (mg/dL (E)).  In this article, both measurements will be cited.  Some conversions are “rounded off” for easy use in the two different units of measure. 

 

Genetics

Every human being has a basic blood cholesterol level that is inherent to them.  This is determined by the biochemical machinery that genetics has provided to them.  Synthesis of cholesterol in the body depends upon a complicated biological pathway of more than twenty enzyme-catalyzed reactions (4).  A 2010 study identified 95 different genetic variations that were associated with deviations in the blood levels of many different lipids (fats) including cholesterol (5).

As mentioned in the introduction, cholesterol is a vital nutrient and human beings can produce all the cholesterol that their bodies need.  The liver and the intestines provide much of it but almost every cell in the body is able to produce cholesterol.  Cholesterol synthesis is tightly regulated.  Too little and there will not be enough to carry out its tremendously important biological roles in the structure of cell membranes and the synthesis of steroid hormones (adrenal hormones, reproductive hormones), bile acids and vitamin D; too much accelerates the deposition of cholesterol into the walls of arteries and the development of cardiovascular disease.  Mammals have a remarkable ability to adapt the cholesterol biosynthetic pathway to meet their changing needs for cholesterol (6,7).   When cholesterol in the diet is low, cholesterol synthesis is upregulated.  Conversely, when the diet is high in cholesterol, the synthesis of cholesterol can be at least partially slowed through feedback inhibition in which higher dietary cholesterol reduces body production (6,8,9).

The basic cholesterol levels for most people who are not ingesting excessive amounts of cholesterol in their diet fall generally within the range of healthy limits.  This means an LDL-cholesterol level less than 3.6 mmol/L (130 mg/dL).  There is no consensus among health experts on a lower limit of cholesterol concentration.  Indeed, recent research found thatcardiovascular risk continues to decrease even down to an LDL-cholesterol level of 0.5 mmol/L (21 mg/dL) with no apparent adverse effects (10).

A small percentage of people have an inherited genetic mutation in one of three genes which is known as familial hypercholesterolemia (FH).  In this condition, LDL-cholesterol levels are greater than 4.9 mmol/L (190 mg/dL).  FH greatly elevates LDL-cholesterol levels throughout life and results in a 22-fold increased risk of coronary artery disease compared to those with an LDL-cholesterol level of below 3.6 mmol/L (130 mg/dL) (11).  However, a study from 2016 concluded that single-gene mutations such as FH account for only 2% of cases of extremely high cholesterol blood levels.  Abnormally high LDL-cholesterol can also be caused by the accumulation of many minor genetic variants that each confer a small increase in LDL; by diet and other lifestyle factors; and by hormonal and kidney diseases.  People with high LDL-cholesterol stemming from one of these alternate causes have a 6-fold greater risk of coronary artery disease than people with healthy LDL-cholesterol levels (11).

IMPORTANT:  Remember that genes are not your destiny.   Environmental factors and individual lifestyles are extremely influential in determining susceptibility to disease.   The way genes are expressed can be transformed by lifestyle choices and environmental influences with significant effects on the health and adaptability of a living being.  Even in FH, the first line of treatment is diet and lifestyle modification (12,13).

 

Age

Children and adolescents are very unlikely to have high LDL-cholesterol levels and, in actual fact, most experience a decrease in cholesterol levels between the ages of 10 and 20 years of age.

 

In young people,

Optimal LDL-cholesterol is less than 2.8 mmol/L (110 mg/dL).

Borderline high is from 2.8 to 3.3 mmol/L (110 to 129 mg/dL).

High is 3.4 mmol/L (130 mg/dL) and higher (14)

 

In adults however, cholesterol rises with age causing LDL-cholesterol increases of about 40% between the ages of 20 and 60 years.  This appears to be due to many small changes such as decreased clearance of LDL-cholesterol from the blood and alterations in its metabolism with normal aging (4,15).

In spite of this aging effect, healthy LDL-cholesterol goals for adults of any age remain the same (14);

Optimal is less than 2.6 mmol/L (100 mg/dL).

Near optimal is 2.6 to 3.5 mmol/L (100 to 129 mg/dL)

Borderline high is 3.6 to 4.1 mmol/L (130-159 mg/dL)

High is 4.2 to 4.9 mmol/L (160 to 189 mg/dL)

Very high is 5.0 mmol/L (190 mg/dL) and above

 

Gender

The rise in LDL-cholesterol levels with age occurs more rapidly in men and this accounts for most of the gender difference in cholesterol levels.  In women, the increase in LDL-cholesterol levels begins to accelerate between the ages of 50 and 60 years and exceeds the levels in men by 55 to 60 years of age (15,4).

Women’s cholesterol levels can also vary with the phase of the menstrual cycle.  This is because cholesterol responds to changes in estrogen levels.  As estrogen levels rise, levels of total cholesterol and LDL-cholesterol fall.  Cholesterol levels are highest before ovulation and lowest at the end of the cycle when menstruation occurs.  Research has found a 19% variation in the total cholesterol of women over the course of their cycle (16).

Menopause has its own effects in women.  At this stage of life, LDL-cholesterol rises, and HDL-cholesterol, the so-called “good cholesterol”, decreases.  The reasons for this are not completely understood but research suggests that menopause causes the loss of protective elements present in younger women.  For instance, estrogen helps remove LDL-cholesterol particles from the circulation and menopause brings with it a decline in estrogen levels.  Additionally, metabolic syndrome, a collection of risk factors for cardiovascular disease including obesity, hypertension and abnormal glucose and lipid metabolism, becomes more prevalent after menopause (17,18,19).

 

Exercise

The effect of aerobic exercise on human LDL-cholesterol blood levels has been unpredictable.  Some studies have found that aerobic exercise will lower LDL-cholesterol levels, but only if body weight is lost.  Other research notes that exercise can change the size of LDL-cholesterol particles, lowering levels of the smaller, more dense LDL particles that are more strongly related to adverse cardiovascular events (20).  On the other hand, the combination of aerobic exercise with resistance training has been found effective in lowering LDL-cholesterol (21).  Other investigations have observed no effect of aerobic exercise on LDL-cholesterol at all.  Additional studies on this subject are needed to fill in the details of how exercise affects cholesterol.

  

Diet

Diet has a substantial influence on levels of lipids in the bloodstream.  The body can balance cholesterol levels under normal conditions, however, a diet high in food derived from animals, including meats, poultry, fish and dairy products, can overwhelm cholesterol regulation (1).

High fat diets are associated with increases in both total cholesterol and LDL-cholesterol along with reductions in HDL-cholesterol.  Long-term high fat diet consumption also leads to a significant increase in body weight (4).  Ketogenic diets, a type of high-fat diet concentrating on animal-sourced foods with only a minimum of carbohydrates from low-starch fruits and vegetables, have also been linked to large increases in levels of total cholesterol and LDL-cholesterol (22).

The exact mechanism for this effect is not completely understood.  Cholesterol is a component of animal-sourced foods and dietary cholesterol may be responsible for some of the increase.  However, research is pointing to other issues in foods originating from animals, such as the presence of saturated fat and animal protein, as the main initiators of raised blood lipid levels (23).  Foods high in saturated fats are especially problematic as they induce the liver to produce more cholesterol than it normally would (24).  Saturated and trans-fats in the diet are also associated with an increase in the risk of dying from heart disease, cancer and cognitive diseases compared to those who consume more unsaturated fats (25).

Conversely, diets consisting of mostly plants dramatically reduce cholesterol levels.  Plant tissues do not contain cholesterol, trans-fats or animal protein.  Saturated fat is also very limited in plants, with coconuts and their oil as well as palm and palm kernel oils being the only significant sources (26).

A 2017 systematic review and meta-analysis examined 30 observational studies and 19 controlled clinical trials.  Consumption of vegetarian or vegan diets was associated with significantly lower total cholesterol, LDL-cholesterol and HDL-cholesterol levels in the blood compared to those consuming omnivorous diets.  Vegan diets, which contain no animal-sourced foods of any kind, resulted in the greatest benefits on lipid levels (26).

A 2015 meta-analysis reviewed eleven studies of vegetarian diets and found that those eating vegetarian experienced significant reductions in total, LDL-cholesterol and HDL-cholesterol along with a corresponding 10% reduced risk of heart disease (27).

Replacing saturated fats with whole carbohydrate-rich foods and unsaturated fats reduces heart disease risk.  Studies show that those replacing only 5% of calories from saturated fat with an equal number of calories from healthier foods reduced their heart disease risk by…

25% if they replaced saturated fat with polyunsaturated fat

15% if they replaced saturated fat with monounsaturated fat

9% if they replaced saturated fat with whole-grain carbohydrates (28)

 

Weight Loss

Although the research on the immediate effects of weight loss on blood lipid levels is sparse, it has been observed that rapid weight loss can sometimes result in transient increases in blood lipid levels. One study of 66 obese women prescribed a weight loss diet for 16 weeks and then a maintenance diet to be continued thereafter.  During the first 8 weeks, cholesterol levels decreased, but, between 8 weeks and 24 weeks, total and LDL-cholesterol increased by 4.2%, and 4.5%, respectively (29).  Another trial followed six obese women who lost an average of 30 kg of weight over 5 to 7 months and maintained the weight loss for the next two months.   Their total cholesterol fell during the first two months of weight loss from an average of 5.49 mmol/L (212 mg/dL) to an average of 3.62 mmol/L (140 mg/dL).  However, during the continuing months of weight loss, their average cholesterol levels rose to 5.95 mmol/L (230 mg/dL).  With weight maintenance, cholesterol came down once again to an average of 4.92 mmol/L (190 mg/dL).  The researchers concluded that the mobilization of fat from body fat storage caused the increased levels which resolved once weight loss stabilized (30).

Studies on fasting have also shown increases in total cholesterol and LDL-cholesterol levels that correspond with the amount of weight lost.  Researchers noted that fasting is accompanied by substantial breakdown of lipids which might explain the observed increases.  In addition, decreased LDL uptake by the liver during fasting might also be contributing to the rise in LDL levels (31).

The takeaway from this is that weight loss may be responsible for transient increases in cholesterol levels.  If you are monitoring your cholesterol as you transition to a healthier diet, it is suggested that you wait until any weight loss has been stabilized for a few weeks before testing your cholesterol levels.

 

Time of Year

Interestingly, studies have shown that cholesterol levels, including total cholesterol, LDL-cholesterol and HDL-cholesterol, generally increase in the fall and winter seasons and decrease in the spring and summer.  These changes appear to occur more frequently in women.  The most striking effects happen in areas of extreme seasonal climactic variation.  For example, people living in Finland experience as much as a 2.59 mmol/L (114 mg/dL) change.  The US National Cholesterol Education Program noted that 25.4% of US men reach lipid levels requiring treatment with medication during the winter season while only 13.5% meet such levels in the summer.  It appears that lowering of physical activity and a decrease in blood volume at the onset of colder months is linked to this effect.  Despite this evidence, seasonal disparities in blood lipids are not taken into account in regular blood test results or in the treatment of high cholesterol levels (32)

 

Laboratory variations

Inaccurate lab tests can also give rise to misleading blood test results.

 

Different test outcomes can arise from the same blood sample from different laboratories

Despite rigorous laboratory certification and proficiency standards, consistency among tests performed in different laboratories can vary significantly.  In one investigation, researchers found that 68% of blood tests executed in two different labs showed substantial differences in results.  Triglyceride levels and red blood cell count exhibited the most consistent test results while white blood cell count and total cholesterol levels displayed the most discrepancies (33).

 

Different test outcomes can arise from blood samples obtained at different times of day or on different days

When blood samples collected early in the day were compared to those taken from the same individuals later in the day, significant differences in results were observed (33).  One study looked at LDL-cholesterol testing in adolescents and revealed large differences between initial and subsequent tests, especially in tests reporting very high results.  Investigators recommended that practitioners should be aware that high LDL-cholesterol results may fall substantially in the absence of any intervention and that treatment decisions should not depend on a single test (34).  Other research concluded that LDL-cholesterol values from a single measurement were more reliable if they were below 3 mmol/L (116mg/dL) or above 4.5 mmol/L (174 mg/dL).  The bottom line here is that repeated measurements should be taken before a stable cholesterol level can be determined (35).

 

Solving the conundrum surrounding cholesterol testing

It is clear that there are numerous influences on the numerical value representing your own unique normal blood cholesterol.   Watch for Part Two of this article that approaches this problem from a different point of view and presents alternate ways to guide decisions aimed at optimizing the health of the cardiovascular system.

 

SOURCES:

1 https://www.heart.org/en/health-topics/cholesterol/about-cholesterol

2 https://my.clevelandclinic.org/health/articles/11920-cholesterol-numbers-what-do-they-mean

3  Ference, B.A., Ginsberg, H.N., Graham, I. et al.  Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.  Eur Heart J April 4, 2017.

4  Uranga, R.M.  Keller, J.N.  Diet and Age Interactions with Regards to Cholesterol Regulation and Brain Pathogenesis.  Curr Gerontol Geriatr Res. 2010; 2010: 219683.  Doi: 10.1155/2010/219683.

5  Teslovich, T.M., Musunuru, K., Smith, A.V. et al.  Biological, clinical and population relevance of 95 loci for blood lipids.  Nature. 5 August 2010; 466: 707-713.

6  https://themedicalbiochemistrypage.org/cholesterol-synthesis-metabolism-and-regulation/

7  Dietschy, J.M., Turley, S.D., Spady, D.K.  Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.  J Lipid Research. 1993; 34: 1637-1659.

8  Mashnafi, S., Plat, J., Mensink, R.P., Baumgartner, S.  Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review.  Nutrients. 2019 Jan; 11(1): 124.

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10  Sabatine, M.S., Wiviott, S.D., Im, K.A., et al.  Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels:  A Meta-analysis.  JAMA Cardiol. 2018; 3(9): 823-828. Doi:10.1001/jamacardio.2018.2258.

11  Khera, A.V., Won, H.-H., Peloso, G.M., Lawson, K.S., Bartz, T.M. et al.   Diagnostic Yield of Sequencing Familial Hypercholesterolemia Genes in Patients with Severe Hypercholesterolemia.  J Am Coll Cardio. 2016; DOI: 10.1016/j.jacc.2016.03.520.

12 Prasher, D., Greenway, S.C., Singh, R.B.  The impact of epigenetics on cardiovascular disease.  Biochem Cell Biol. 2020 Feb; 98(1): 12-22. Doi: 10.1139/bcb-2019-0045.

13 https://www.mayoclinic.org/diseases-conditions/familial-hypercholesterolemia/diagnosis-treatment/drc-20353757

14  https://myhealth.alberta.ca/Health/Pages/conditions.aspx?hwid=hw207814

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16  https://www.nih.gov/news-events/news-releases/womens-cholesterol-levels-vary-phase-menstrual-cycle

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18  Ben Ali, S., Belfki-Benali, H., Aounallah-Skhiri, H., Traissac, P., Maire, B., Delpeuch, F., Achour, N., Ben Romdhane, H.  Menopause and metabolic syndrome in tunisian women.  Biomed Res Int. 2014; 2014: 457131. Doi: 10.1155/2014/457131.

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21  Mann, S., Beedie, C., Jimenez, A. Differential effects of aerobic exercise, resistance training and combined exercise modalities on cholesterol and the lipid profile: review, synthesis and recommendations. Sports Med. 2014; 44(2): 211-221. Doi: 10.1007/s40279-013-0110-5.

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24  https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/the-skinny-on-fats

25  Wang, D.D., Li, Y., Chiuve, S.E., Stampfer, M.J., Manson, J.E., Rimm, E.B., Willett, W.C., Hu, F.B.   Association of specific dietary fats with total and cause-specific mortality. JAMA Intern Med. 2016 Aug 1; 176(8): 1134-1145. Doi: 10.1001/jamainternmed.2016.2417.

26  Yokoyama, Y., Levin, S.M., Barnard, M.D. Association between plant-based diets and plasma lipids: a systematic review and meta-analysis.  Nutr Rev. 2017 Sep 1; 75(9): 683-698. Doi: 10.1093/nutrit/nux030.

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28  Li, Y., Hruby, A., Bernstein, A.M., et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study. J Am Coll Cardiol. 2015;66:1538-1548.

29  Andersen, R.E., Wadden, T.A., Bartlett, S.J., Vogt, R.A., Weinstock, R.S.  Relation of weight loss to changes in serum lipids and lipoproteins in obese women.  Am J Clin Nutr. 1995 Aug; 62(2): 350-357. Doi: 10.1093/ajcn/62.2.350.

30  Phinney, S.D., Tang, A.B., Waggoner, C.R., Tezanos-Pinto, R.G., Davis, P.A.  The transient hypercholesterolemia of major weight loss.  Am J Clin Nutr. 1991 Jun; 53(6):1404-1410. doi: 10.1093/ajcn/53.6.1404.

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32 Ockene, I.S., Chiriboga, D.E., Stanek III, E.J., et al. Seasonal Variation in Serum Cholesterol Levels: Treatment Implications and Possible Mechanisms. Arch Intern Med. 2004;164(8):863–870. doi:10.1001/archinte.164.8.863.

33  Kidd, B.A., Hoffman, G., Zimmerman, N., et al. Evaluation of direct-to-consumer low-volume lab tests in healthy adults. J Clin Invest. 2016. Doi: 10.1172/JCI86318.

34  Freedman, D.S., Wang, Y. Claire, Dietz, W.H., Xu, J.-H., Srinivasan, S.R., Berenson, G.S.  Changes and variability in high levels of low-density lipoprotein cholesterol among children.  Pediatrics. 2010 Aug; 126(2):266-273. Doi: 10.1542/peds.2009-3454.

35    Bookstein, L., Gidding, S.S., Donovan, M., Smith, F.A.  Day-to-day variability of serum cholesterol, triglyceride, and high-density lipoprotein cholesterol levels. Impact on the assessment of risk according to the National Cholesterol Education Program guidelines.  Arch Intern Med. 1990 Aug; 150(8):1653-1657.