Cholesterol conundrum

36. The Cholesterol Confusion !

Although we doctors advise people to get their cholesterol (especially LDL cholesterol and other  lipids) checked and keep it under control with diet and exercise, and also sometimes advise to take drugs like statins in addition, the “cholesterol theory” has come under fire in a lot of scientific and social media.

The issues which have raised a controversy are :

1. Is “cholesterol in food” harmful ? Does it raise cholesterol level in blood? Should it’s intake be restricted?
2. Is high intake of “fats in food” harmful ?
3. Is “high cholesterol in blood” the cause of atherosclerosis, leading to coronary heart disease ?
4. Are statins good medicine?

As an answer to the first question, a message on social media says :

“Cholesterol is finally officially removed from Naughty List. The US government has finally accepted that cholesterol is not a nutrient of concern doing a U-turn on their warnings to us to stay away from high-cholesterol foods since the 1970s to avoid heart disease and clogged arteries.
This means eggs, butter, full-fat dairy products, nuts, coconut oil and meat have now been classified as *safe* and have been officially removed from the nutrients of concern list.”

This is a dangerous half truth which needs to be addressed and clarified.

Yes, the first part of the message is true; 300gm per day limit on dietary cholesterol is relaxed by the2015-2020 US guidelines. But this is nothing new or extra-ordinary, because dietary cholesterol- that is raw cholesterol that is present in foods like egg yolk, does not contribute much to raise blood cholesterol in the quantity consumed (for example each egg yolk has 186 mg of cholesterol). It is the saturated and trans-fats in food which really contribute to raising blood cholesterol. 

Hence, the error is in the second part which lists butter, full-fat dairy products, and meat as *safe* and have been officially removed from the nutrients of concern list.

Nothing can be farther from the truth. These foods  have NOT “been officially removed from the nutrients of concern list” as the message falsely proclaims.

This is because, butter, full-fat dairy products, and meat contain large amounts of saturated fats, besides containing cholesterol, and as said earlier, it is the saturated and trans-fats in food which really contribute to raising blood cholesterol. 

The US guidelines can be seen from: http://health.gov/news/dietary-guidelines-digital-press-kit/2016/01/top-10-things-you-need-to-know/

The relevant sections reproduced verbatim, say the following:

5.      Healthy eating patterns limit added sugars. Less than 10% of your daily calories should come from added sugars. ChooseMyPlate.gov provides more information about added sugars, which are sugars and syrups that are added to foods or beverages when they are processed or prepared. This does not include naturally occurring sugars such as those consumed as part of milk and fruits.

6.      Healthy eating patterns limit saturated and trans fats. Less than 10% of your daily calories should come from saturated fats. Foods that are high in saturated fat include butter, whole milk, meats that are not labeled as lean, and tropical oils such as coconut and palm oil. Saturated fats should be replaced with unsaturated fats, such as canola or olive oil

The confusion and error stems from mixing up foods like eggs containing ONLY cholesterol with foods like butter, full-fat dairy products, and meat which have saturated fat and trans-fat, AND cholesterol in them.

So one must distinguish between foods containing ONLY cholesterol, like eggs and seafood (like shrimp and lobster) and foods containing BOTH cholesterol and saturated fats & trans fats like butter, full-fat dairy products and meat. They cannot be put in the same basket.

While the former can be had in moderate amounts, the recommendation for saturated fats is not more than 10% of total calories, and trans fats - as low as possible. And yes, sugar should be restricted.

Coming to the question number 2:

About the advice on fats, both, the proponents and opponents have strong arguments supporting their views.

Contrary to recommendation from AHA mentioned above, recent studies like PURE study show that saturated fats are good for us. However, there are many flaws in the PURE study.

Anyway, in the light of conflicting opinions on this, what a patient recently told me was revealing. (One always learns from patients).

He was a 102 Kg American with symptoms of angina due to coronary artery disease. He said that when his meal had meat, pork, cheese or butter, slightest exertion after the meal caused chest discomfort, whereas when he ate a Mediterranean like diet (fruits, salads, fish, nuts whole grains etc) he could walk a mile without chest discomfort.

Saturated fats (like in cheese, meat etc) are known to increase the thrombogenicity (tendency to clot) of blood and inability of coronary arteries to relax (endothelial dysfunction).

This was a direct evidence of the harmful effects of diet high in saturated fats in a patient with coronary disease.

Hence large consumption of bad quality fats (meats, cheese, butter, chicken or fried food etc) is not a good idea especially if you are above 30 or already have coronary artery disease or risk factors like abdominal obesity, physical inactivity, hypertension, diabetes, abnormal lipids (cholesterol), smoking, family history of coronary heart disease, etc. whereas consumption of moderate amounts of good quality fats (olive oil, fish, nuts) would be ok.

Trans fats are the worst and should be minimum in diet.

Coming to the question number 3:

 Is high cholesterol in blood the cause of atherosclerosis, leading to coronary heart disease ?

1. Well, firstly, cholesterol is needed by the body. It is an essential component of cell membranes and a precursor of bile acids and steroid hormones. Cholesterol is also vital for neurological function. Most of our body’s cholesterol is made in the liver. The rest is obtained from foods –especially those that are high in saturated and trans fats. That’s a problem because these fats can cause our liver to make more cholesterol than it otherwise would. For some people, this added production means they go from a normal cholesterol level to one that’s unhealthy.

So although cholesterol is required by the body and is mostly produced in the liver, our dietary and physical activity habits alter the levels of not only cholesterol but other circulating fats in the blood to pose risk.

2. Secondly, the most clear cut and direct proof that too much cholesterol can cause heart disease is in people with genetic or inherited high low density lipoprotein cholesterol (LDLC) (above 190 mg %).  YES, in such people cholesterol is a direct and main CAUSE of atherosclerosis leading to coronary disease.

3. Thirdly, for most other people, cholesterol, especially LDL cholesterol is a risk factor, a strong risk factor.

A risk factor is an abnormality which is strongly associated with a disease, but for which an exact cause and effect relationship is not established.

In most people, atherosclerosis is a disease of multiple factors in which cholesterol is a team player, a very important one. It is one of the risk factors like hypertension, diabetes, smoking, physical inactivity, central obesity, unhealthy diet, etc which singly or in combination increase one’s chances of having atherosclerotic coronary artery disease (CAD). The more the number of risk factors, the more abnormal each one of them is and the longer it remains untreated, the greater the likelihood of having the disease.

Different set of risk factors operate in different people. In some patients, high cholesterol alone may indeed be the dominant cause; for example people with genetically very high cholesterol levels; in others, hypertension is the dominant cause, for example in the Japanese; in still others, cigarette smoking may be the dominant cause.  But in most people multiple factors act synergistically to cause CAD.

4. Fourthly, although we do not know the exact cause of atherosclerotic disease in every one, we know the 2 key events that lead to the disease.

a. Inflammation of the arteries, especially its inner lining making it “sticky” to ‘mop up’ circulating lipoproteins.

b. Accumulation of these cholesterol-rich lipoproteins within the arterial lining at certain sites.

5. So, the fundamental cause of atherosclerosis is injury and inflammation of the inner lining of arteries (making it sticky) due to above mentioned risk factors and ingress of cholesterol containing lipoproteins into this lining creating more inflammation and atherosclerosis

6. Even if we assume that cholesterol is not the cause of atherosclerotic disease, studies done on more than 2 million people with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent log-linear association between the amount of LDL-C  in the blood along with the duration for which the body is exposed to it and the risk of atherosclerotic disease like CAD.

Not only that, but also that reducing or correcting it (whether by lifestyle changes or statins) reduces the chances of disease, whatever the initial cholesterol levels. These measures not only reduce cholesterol levels in the blood but also cause the fatty deposits in arteries to stabilize and even regress, which can REVERSE CORONARY DISEASE.

Relatively modest 17% drop in cholesterol level could lead to a 40% decrease in coronary death rate for men with cholesterol levels initially in the range of 221-244 mg% !

7. The final arbitrator is what we see in our patients. Surely, we see in our day to day practice the tremendous benefit  of life style and statins stabilizing and regressing the disease.

But what about the study published in the British Medical Journal recently and displayed all over the media,  (BMJ Open 12 June 2016. Volume 6, Issue 6), concluding that there was a lack of an association or an inverse association between low-density-lipoprotein cholesterol (LDLC) and mortality in the elderly (above 60). 

This study has many flaws, such as the following :

•          There is the possibility that many studies may have been missed out from this paper. The review searched only a single literature database, excluded studies available in non-English language, and excluded studies where the title and abstract did not appear to contain information on the link between LDL and mortality in older adults.

•          The study only looked at the link in older adults aged over 60, whereas LDL-cholesterol levels may show stronger linkage with long-term mortality in younger adults.

•          There were varying degrees of interfering (‘confounding’)  factors that could be having an influence on the link between LDL and mortality, such as smoking, alcohol, socioeconomic factors, presence of conditions, and use of medications which were not incorporated into the studies.

•          Only LDL cholesterol was examined. As written below, there are other lipid parameters which play a part in people with apparently “normal” LDL levels.

•          The endpoint of the review is all-cause mortality – not cardiovascular mortality with which high LDL-cholesterol has stronger links.

•          Most important is there is no detail on the use of statins in this population. It may be possible that people found to have the highest LDL cholesterol levels at the study's start may have then been started on statins, and this could have dramatically cut their mortality risk.

•          Finally, this could well be a preconceived view of the authors regarding the role of cholesterol, given that 4 of the study authors have previously written book(s) criticizing "the cholesterol hypothesis", and that nine of the authors are members of THINCS – The International Network of Cholesterol Skeptics !

Ok, but we find some people with “low cholesterol” have heart disease and some with “high cholesterol” don’t have disease. Why ?

This is because of multiple reasons listed below:

1. Other risk factors (like smoking in the young, or hypertension, diabetes, central obesity, life style etc) impacting the effect of cholesterol, may play a predominant role in some people.
2. The NUMBER of LDL particles is more important than the AMOUNT of cholesterol in them:

Cholesterol is predominantly carried in the blood in particles called LDL particles. Each LDL  particle carries a certain amount of cholesterol. The amount of cholesterol carried by LDL particle varies between individuals and in the same individual at varying times. It is the number of these particles and not absolute amount of cholesterol that is best related to atherosclerosis.

Usually, they match. That is, the amount of cholesterol correlates with the number of particles circulating in blood.

Hence instead of estimating the number of particles (which is a tedious and expensive measurement to do in practice) we measure the cholesterol in blood, which is more easily done in our lipid tests.

However, in some people the two may not correlate.

For example two persons with same amount of cholesterol may have it carried by different kinds of particles. (See figure) In one (A), cholesterol is predominantly carried by a small number of large sized  particles. In person B, it is carried by small sized particles which are large in number to carry the same amount of cholesterol.

The latter, also called small dense LDL particles are more atherogenic both because of the number and the small size (besides other factors). The former are less atherogenic due to the small number, though the amount of cholesterol is the same.

Hence two persons with same amount of cholesterol can have different propensities to develop coronary disease due to difference in the number of LDL particles.

Hence a person with high cholesterol may escape from disease (due to small number of large sized particles) and a person with low cholesterol may suffer because of large number of small sized particles.

3. Other Lipoprotein  particles : Although as we said earlier, LDL carries about 90% of cholesterol in blood, in some people, other lipoproteins may carry significant amount of cholesterol, such as Lp(a), Intermediate and very low density lipoproteins (IDL,VLDL etc). Thus although the LDLC or number of LDL particles may be average or ‘normal’, the TOTAL number of lipoprotein (LP) particles may be high, causing the disease. This is best known by the amount of apoB in blood, because each LP particle is tagged with one apoB.
4. HDL cholesterol : Recent studies have found that the quality of HDLC and the number of HDL particles may be protective against atherosclerosis. In other words, low HDL efflux capacity or low HDL particle number could be the risk factors in some people.

In practice, since LDL cholesterol can be easily measured, since it correlates with particle number in most people, is seen to be associated with heart disease in a vast majority of population and since particle number cannot be easily measured, it is most commonly utilized as a risk factor and a target for treatment.

However the amount or mass of cholesterol or its level in blood may not correspond with the  number of particles in all as seen above. Also, as seen above, other factors may impact its effect.

That is why studies done on cholesterol as a risk or causative factor for heart disease may show contrasting results and hence the controversy over “the cholesterol hypothesis”. 

Hence, although cholesterol, especially LDLC is a causative factor in most people, in some it may be the number of particles or other lipid abnormalities or risk factors that may be playing a role.

In them, just knowing LDLC may not be enough and tests like apoB (which gives an idea about TOTAL number of LP particles) or non HDLC or Lp(a), or HDL particle number and efflux capacity etc may be required.

Figure : Patient A (left panel) with predominance of large sized LDL particles and Patient B (right panel) with predominance of small sized LDL particles. Although the total cholesterol CONTENT in both is the same, patient B has more NUMBER of particles putting him at higher risk although the cholesterol level in blood is same as patient A.

Finally, question number 4 : Are statins good medicine?

The answer in one line is for prevention of coronary heart disease, nothing in the history of medicine has ever been shown it more convincingly.

More on statins in another chapter.

Thus, the cholesterol story is neither a simple yes or a simple no. One should understand its intricacies and ramifications. It is definitely not a ‘scam’, but a continuing saga of human endeavor in pursuit of solving the mystery that is atherosclerotic coronary heart disease.