LDL, chylomicrons, HDL, and atherosclerosis: A lazy Sunday theory

Notes:
  - This post is a joke, admittedly a weird one, which is why it is labeled “humor” and is filed under “Abstract humor”.
  - I apologize for this spoiler. Some people probably like humor posts better if they do not know what they are in advance, but several others may think that reading a post like this is a waste of their time. If you are in the latter category, move on to another post! If not, here it goes …

***

Today I was spending some time under the sun, in one of the year’s 364 sunny days in Laredo, Texas. The goal was to see if I could obtain a precise count of the number of advanced glycation endproducts (a.k.a. AGEs) that would form as my skin was exposed to the sun’s damaging rays.

Then I read a post by Peter at Hyperlipid, and inspiration consumed me. A new theory was born regarding the interplay of LDL, chylomicrons, HDL, and atherosclerosis. By the way, Peter is a fat genius, by which I mean a genius regarding all fat issues – who happens to be thin.

A key observation forms the main pillar on which this new theory solidly rests:

The endothelium gaps, which let atherogenic particles enter into the forbidden area and do their damage, are around 25 nanometers in diameter. And what is the typical size of LDL particles? You guessed it, 25 nanometers in diameter! And guess what more, quite a few of the chylomicrons, another group of particles that would elicit immediate revulsion in any normal human being, are even smaller than 25 nanometers in diameter; those atherogenic pests!

So here is the theory, in a nutshell. A 500-page book will clearly be needed to discuss it in more detail.

The Devil created LDL particles to kill us all. But LDL particles were not such effective killers, because the Devil, trying to pack as much killer cholesterol into them, ended up making them too big! At 25 nanometers in diameter, on average, they basically had to squeeze their way into the forbidden area.

Since LDL particles were not doing a good enough job, the Devil also created chylomicrons, and those chaotic pests come in all sizes. In fact, it is well known that the word chylomicron has a Greek origin: chylo = killer, micron = particle (Deth & Disis, 1999; full reference at the end of this post).

And, needless to say, LDL particles and chylomicrons are fat particles that make the blood kind of taste and smell like butter, a toxic substance often fed to laboratory rats and known for its powerful carcinogenic properties among all living creatures except descendants of Vlad the Impaler. The latter has long been rumored to have been one of the Devil's best buddies, so no surprise there.

Michael the Archangel, who dislikes the Devil, and usually takes a hands-on approach to dealing with those he dislikes, the Devil in particular, gave us HDL particles. If you have any doubts about Michael’s hands-on approach, check the picture below (from: Wikipedia), which clearly shows what Michael had already done to the Devil. And that was over a relatively minor disagreement.

And don’t think about trying to discredit this theory by asking why HDL particles are so small compared with LDL particles and chylomicrons! This is easy. For the same reason that David was small and Goliath big!

But those nasty particles, the LDLs and chylomicrons, weren't only two big bullies, they were two against one. HDL particles were doing a valiant job at fighting the damage done by the Devil’s two evil particles, but not quite enough to save everybody from atherosclerosis.

Michael cried foul, and threatened to give the Devil another lesson. God, seeing this, said: Michael, no, mankind must be given a choice! If men and women want to gorge on the fatty flesh of the beasts they savagely slaughter, let them sin and face the consequences.

And so it was.

This theory probably needs some adjustments and refinements based on analysis of refereed research, especially solid research supported by drug manufacturers, and consultation with the most interesting man in the world. But I am pretty confident it can, after adjustments and refinements, pass the test of time.

The only nagging problem is the Original Sin. To the best of my knowledge, it was not eating the fatty flesh of beasts. It was eating a very sweet apple …

Reference:

Deth, R., & Disis, M. (1999, Feb 31). The origins of killer lipids: An evolutionary-theological perspective. The Lipid Review, 123(7), 77-66.

A trip to Europe: Some health-related routines and observations

Every year I travel to Europe on business, normally once or twice a year. These trips usually involve meetings with engineers, researchers, and project managers from various European countries; often 5 to 10 countries are represented.

Here are some of my notes on a recent trip to Europe. In this trip I spent time in two cities: Amsterdam, Netherlands and Antwerp, Belgium. Below is a set of the photos I took in Antwerp, of a statue depicting the roman soldier Silvius Brabo holding the severed hand of the giant Druon Antigoon.

According to legend Druon Antigoon had terrorized and extorted the people of Antwerp, cutting off the hands of several people and throwing them in the nearby Scheldt River, until the brave Silvius Brabo came into the scene and not only cut off the giant’s hand but also killed him.

This legend has probably been concocted toward the end of the Roman Empire, largely by the Romans, who first established Antwerp as a Roman outpost.

After this small digression, here are some health-related routines that I followed during this trip, and some of my main observations regarding diet and health issues.

On the plane:

    - The meals were a festival of hyperglycemic and pro-inflammatory refined carbohydrates, unhealthy vegetable oils, and sugars – white bread, pasta, various sweets, pretzels, chips loaded with supposedly healthy omega 6 fats, margarine etc. I skipped all of the snacks and one of the meals, the breakfast. At the main meal of each flight I ate only meat, veggies, and some of the fruits.

    - The flights over and back were very comfortable since I was water-fasting most of the time. Not a hint of indigestion or abdominal discomfort of any kind. These were 9 to 10 hour flights, from Houston to Amsterdam and back.

At business luncheons:

    - The idea of having a sandwich for lunch seems to be getting popular in Europe. At least I have been seeing that happening more and more often lately. At these sandwich luncheons, I ate only the content of some sandwiches (basically cold cuts, cheese and veggies), and left the bread slices untouched.

    - Some people noticed that I was not eating bread. I told them about insulin, lectins etc. A few looked at me as though I was insane; others with a disapproving look – dontchano, the lipid hypothesis!? A notable exception was a German gentleman who said that Germans were too pragmatic not to notice that they were getting fat on low fat diets, and are now reverting back to their staple diet of meats, fish, vegetable stews, and cheese.

At restaurants for dinner:

    - This was fairly easy. I ate basically fish or meat dishes with veggies, and enjoyed them a lot. I skipped the deserts; again much to the surprise of some of my European colleagues.

    - Skipping the desserts seems to have helped me cope with jetlag a lot better than I usually do. On my second day in Europe I slept quite well, and was unusually rested on the next day.

At the hotel:

    - The breakfast buffets were a mix of: (a) breads, pastries, sweetened cereals, sugary items, and fruits; and (b) meats (often cured), some fish, cheeses, eggs, nuts, and some veggies. There were also fruit juices. I had solid breakfasts with (b)-type items, with a few fruits added (cantaloupe and berries). I had regular coffee with cream and no sugar, and stayed away from fruit juices.

    - I did not use soap, shampoo etc. at the hotel; just plain water. Occasionally the soap used in hotels is very caustic, or rich in other chemicals, causing rashes. I stuck with showers and had no baths, as sometimes the bathtubs are not properly cleaned after their last use.

    - At the end of my trip I took a train from Antwerp to Amsterdam, and stayed at a hotel near the Schiphol Airport (which has its own train station) since my flight back to the U.S. was in the morning. I had dinner by myself at the hotel, which was easy. I stopped at a place called Food Village at the Airport (visible from the Airport’s main entrance) and bought a water bottle, a piece of Gouda cheese, a can of sardines, and a box of seaweed. That was a very good dinner, and cost me about 6 euros.

The outcomes for me:

    - I had no hint of indigestion at all throughout the trip, in spite of eating way more cheese than I normally do. The cheese that I ate was natural, aged cheese, not the processed kind.

    - I had no need for more or less use of the bathroom than I usually do, and remained “regular” throughout the trip. No sign of constipation at all.

    - I had no body odor (at least none that I could notice), even though I used no soap. My hair was fine too; I used no shampoo or conditioner.

    - Jet lag problems were less pronounced than they usually are when I travel to Europe. The time difference is about 7 hours from Texas. Usually, I tend to feel very sleepy in the afternoon and wide awake around 3 am. Not this time.

    - In spite of not exercising for about 7 days, except for walking, I was able to lift slightly heavier weights at a workout the day after my return than I did before my trip.

    - According to the scale, I lost 1 pound during this trip. I do not know whether this was body fat or just water. It is unlikely that there was any muscle loss.

From what I could see, Europeans are generally thinner than Americans (particularly Texans), and also seem to be healthier. None of the people I met, not one, was clearly obese. On the other hand, the majority seemed to be somewhat overweight.

My impression was that the Europeans consume lesser amounts of refined carbohydrates and sugars than Americans, on a weekly basis, even though they currently consume more of those items than they should, in my opinion.

Consumption of vegetable oils other than olive oil is also lower than in the U.S; consumption of butter and cheese seems to be a lot higher.

From my conversations with several people during this trip, it seemed that the health of Europeans, like that of their American counterparts, is strongly correlated with the extent to which they are overweight. The more body fat, the more common was to hear complaints about pain here or there, fatigue, degenerative diseases, or talk about surgeries.

More on the Harvard study on saturated versus polyunsaturated fats

This is a follow up on this post, which addressed the main argument put forth in a recent BBC article. The BBC article argued that people should replace saturated with polyunsaturated fats to reduce their risk of heart disease.

Let us take a look at the actual Harvard study itself (i.e., the study discussed in the BBC article). The Harvard study is linked here.

This post, by Stephan Guyenet, already pointed out several problems with the study. Stephan actually reviewed the studies used in the meta-analysis, and also some that were excluded in the meta-analysis and that he believes should have been included.

Here are a few other problems, in addition to the ones already pointed out by Stephan:

One thing that looks suspicious about this Harvard meta-analysis study is that they say that: “Statistical evidence for substantial between-study heterogeneity was not present (Q-statistic p = 0.13; I2 = 37%).”

A meta-analysis is a study that essentially summarizes, in a statistically sophisticated way, a bunch of other studies (the “sourced” studies). Too much between-study heterogeneity (i.e., widely disparate results among sourced studies) is undesirable, because it can bias the results.

The problem is similar to that of trying to summarize net worth figures (e.g., by calculating their average) in a middle class neighborhood that happens to have a few billionaires living in it. The heterogeneity in wealth may lead to a wildly overestimated average.

Now, we know that p values go down with sample size, and are usually high with small samples unless the effect measured by the statistic is very strong, regardless of the statistic used.

Well, with a sample of only 8 studies, their p value (associated with the Q statistic) is close to being significant at the 0.05 level!

If this sample of sourced studies were a little higher (say, 20), there would be significant between-study heterogeneity, which would call the meta-analysis into question. This is a big problem, since a good meta-analysis is expected to include a large number of studies (e.g., greater than 100), and this one included only 8 studies.

Moreover, to the best of my knowledge, the Q statistic is not very reliable when used with small samples, due to its low power as a test of heterogeneity. This makes the p value reported even more problematic.

Finally, the sourced study with the largest sample (n = 9,057; thus possibly the most credible), indicated as “Minnesota CS” on Figure 2 of the Harvard study, found increased risk of heart disease associated with increased consumption of polyunsaturated fats and reduced consumption of saturated fats.

Reference:

Mozaffarian, D., Micha, R., & Wallace, S. (2010). Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS Med., 7(3): e1000252. doi: 10.1371/journal.pmed.1000252.

BBC article's advice: Replace saturated with polyunsaturated fats

The BBC article is here. It is based on meta-analysis of eight previous studies conducted by Harvard researchers, which the article states cover more than 13,000 people. The article also says that: “… [saturated] fats raise the levels of bad cholesterol that block the arteries to the heart.” They are of course referring to LDL cholesterol as the "bad cholesterol".

Sourcing bias is a notorious problem with meta-analyses (i.e., the choice of studies to use in a meta-analysis). Another problem is that you cannot tell what the studies sourced controlled for. Consider a study that compares health markers for smokers and non-smokers, where the smokers eat more saturated fat than the non-smokers. This study may confuse the effect of smoking with that of saturated fat consumption. To be reliable, the study must analyze the effect of saturated fat consumption, controlling for smoking habits.

There are other statistical issues to be considered in meta-analyses. For example, some of the sourced studies may take nonlinear relationships into consideration and others not. In multivariate analysis studies, nonlinearity may lead to significantly different results from those obtained through more conventional linear analyses.

Finally, reaching misleading results with sound statistical analyses is not that hard. As my age went from 1 to 20 years, my weight was strongly correlated with the price of gasoline. Yet, neither my weight caused the price of gasoline, nor the other way around. When you look at an individual study, not a meta-analysis, you can at least try to identify the possible sources of bias and mistakes.

Having said that, a solid refutation of the main argument in the article can be made from many angles. Here is a simple refutation based on what I would call the “HDL cholesterol angle”, with links to posts and various refereed publications:

- Increasing HDL cholesterol levels, especially beyond 60 mg/dl, dramatically decreases the risk of heart disease; and this is an almost universal effect in humans. This reduction in risk occurs even for people who suffer from diabetes and familial hypercholesterolemia. The latter is a genetic condition that is associated with very elevated LDL cholesterol and that is rare, typically afflicting 1 in 500 people in its heterozygous (and most common) form.

- Increasing consumption of saturated fats (present in: lard, fatty meat, coconut oil) and dietary cholesterol (from: fish, organ meats, eggs), while decreasing consumption of refined carbohydrates (e.g., pasta, white bread) and sugars (e.g., table sugar, high fructose corn syrup), significantly increases HDL cholesterol for the vast majority of people. Neither omega-6 nor omega-3 polyunsaturated fats lead to the same results. Omega-3 fats do reduce triglycerides, and increase HDL somewhat, but their effect on HDL pales in comparison with that of saturated fats. Excessive consumption of omega-6 fats is associated with chronic inflammation and related health problems.

- With the exception of cases involving familial hypercholesterolemia, there is no conclusive evidence that LDL cholesterol levels are associated with heart disease. Two widely used online calculators of risk of heart disease, based on the Framingham Heart Study and the Reynold Risk Score, do not even ask for LDL cholesterol levels to estimate risk. And that is not because they calculate LDL cholesterol based on other figures; they do not ask for VLDL cholesterol or triglycerides either.

After reading the BBC article again, it is clear that they are re-stating, in general terms, Rudolph Virchow’s mid-1800s lipid hypothesis. And they do so as if it was big news!

New Review of Controlled Trials Replacing Saturated fat with Industrial Seed Oils

Readers Stanley and JBG just informed me of a new review paper by Dr. Dariush Mozaffarian and colleagues. Dr. Mozaffarian is one of the Harvard epidemiologists responsible for the Nurse's Health study. The authors claim that overall, the controlled trials show that replacing saturated fat with polyunsaturated fat from industrial seed oils, but not carbohydrate or monounsaturated fat (as in olive oil), slightly reduces the risk of having a heart attack:

These findings provide evidence that consuming PUFA in place of SFA reduces CHD events in RCTs. This suggests that rather than trying to lower PUFA consumption, a shift toward greater population PUFA consumption in place of SFA would significantly reduce rates of CHD.

Looking at the studies they included in their analysis (and at those they excluded), it looks like they did a nice job cherry picking. For example:

• They included the Finnish Mental Hospital trial, which is a terrible trial for a number of reasons. It wasn't randomized, properly controlled, or blinded*. Thus, it doesn't fit the authors' stated inclusion criteria, but they included it in their analysis anyway**. Besides, the magnitude of the result has never been replicated by better trials-- not even close.
• They included two trials that changed more than just the proportion of SFA to PUFA. For example, the Oslo Diet-heart trial replaced animal fat with seed oils, but also increased fruit, nut, vegetable and fish intake, while reducing trans fat margarine intake. The STARS trial increased both omega-6 and omega-3, reduced processed food intake, and increased fruit and vegetable intake. These obviously aren't controlled trials isolating the issue of dietary fat substitution. If you subtract the four inappropriate trials from their analysis, which is half the studies they analyzed, the significant result disappears. Those four just happened to show the largest reduction in heart attack mortality...
• They excluded the Rose et al. corn oil trial and the Sydney Diet-heart trial. Both found a large increase in total mortality from replacing animal fat with seed oils, and the Rose trial found a large increase in heart attack deaths (the Sydney trial reported total mortality but not CHD deaths).

The authors claim, based on their analysis, that replacing 5% of calories as saturated fat with polyunsaturated fat would reduce the risk of having a heart attack by 10%. Take a minute to think about the implications of that statement. For the average American, that means cutting saturated fat nearly in half to 6% of energy, which is a challenge if you want to eat a normal diet. It also means nearly doubling PUFA intake, which will come mostly from seed oils if you follow the authors' advice.

So basically, even if the authors' conclusion were correct, you overhaul your whole diet and replace natural foods with industrial foods, and...? You reduce your 10-year risk of having a heart attack from 10 percent to 9 percent. Without affecting your overall risk of dying. The paper states that the interventions didn't affect overall mortality.


* Not even single blinded.  Autopsies were not conducted in a blinded manner. Physicians knew which hospital the cadavers came from, because autopsies were done on-site. There is some confusion about this point because the second paper states that physicians interpreted the autopsy reports in a blinded manner. But that doesn't make it blinded, since the autopsies weren't blinded. The patients were also not blinded, though this is hard to accomplish with a study like this.

** They refer to it as "cluster randomized", which I feel is a misuse of that term.  The investigators definitely didn't randomize the individual patients: whichever hospital a person was being treated in, that's the food he/she ate. There were only two hospitals, so "cluster randomization" in this case would just refer to deciding which hospital got the intervention first. I don't think this counts as cluster randomization.  An example of cluster randomization would be if you had 10 hospitals, and you randomized which hospital received which treatment first.  It's analogous to individual randomization but on a group scale.

PepsiCo to reduce sugar and fat in products

I guess PepsiCo is moving ahead of the competition, but in a snail pace and in a very, very politically correct way. Will this help in any way? I doubt. It is just too little, too late. See article here.

The article states that:

The company also set two goals for the next 10 years: to cut the average added sugar per serving by 25 percent and saturated fat per serving by 15 percent, in addition to adding more whole grains, fruits, vegetables and low-fat dairy into its array of products.

While it is nice to see more of a focus on sugar than on saturated fat, I would have preferred to see something like this:

The company also set two goals for the next 5 years: to cut the average added sugar per serving by 95 percent and increase saturated fat per serving by 50 percent, in addition to adding more vegetables and full-fat dairy into its array of products.

What would happen? Well, Indra Nooyi is a very smart CEO, and the company has many competent people. They know that they would probably lose enough customers to go out of business … or become the Apple of their industry.

The bottom line is that, if you want to improve your health, you should generally avoid any food or liquid that is highly industrialized.

Maybe PepsiCo should add unprocessed coconut water to their portfolio of drinks.

Fatty Liver: It's not Just for Grown-ups Anymore

The epidemic of non-alcoholic fatty liver disease (NAFLD) is one of my favorite topics on this blog, due to the liver's role as the body's metabolic "grand central station", as Dr. Philip Wood puts it. The liver plays a critical part in the regulation of sugar, insulin, and lipid levels in the blood. Many of the routine blood tests administered in the doctor's office (blood glucose, cholesterol, etc.) partially reflect liver function.

NAFLD is an excessive accumulation of fat in the liver that impairs its function and can lead to severe liver inflammation (NASH), and in a small percentage of people, liver cancer. An estimated 20-30% of people in industrial nations suffer from NAFLD, a shockingly high prevalence (1).

I previously posted on dietary factors I believe are involved in NAFLD. In rodents, feeding a large amount of sugar or industrial seed oils (corn oil, etc.) promotes NAFLD, whereas fats such as butter and coconut oil do not (2). In human infants, enteric feeding with industrial seed oils causes severe liver damage, whereas the same amount of fat from fish oil doesn't, and can even reverse the damage done by seed oils (3). [2013 update: obesity is probably the main contributor to NAFLD.  Obesity is associated with ectopic fat deposition in a number of organs, including the liver]

So basically, I think excessive sugar and industrial oils could be involved NAFLD, and if you look at diet trends in the US over the last 40 years, they're consistent with the idea.

I recently came across a study that examined the diet of Canadian children with NAFLD (6). The children had a high sugar intake, a typical (i.e., high) omega-6 intake, and a low omega-3 intake. The authors claimed that the children also had a high saturated fat intake, but at 10.5% of calories, they were almost eating to the American Heart Association's "Step I" diet recommendations**! Total fat intake was also low.

High sugar consumption was associated with a larger waist circumference, insulin resistance, lower adiponectin and elevated markers of inflammation. High omega-6 intake was associated with markers of inflammation. Low omega-3 intake was associated with insulin resistance and elevated liver enzymes. Saturated fat intake presumably had no relation to any of these markers, since they didn't mention it in the text.

These children with NAFLD, who were all insulin resistant and mostly obese, had diets high in omega-6, high in sugar, and low in omega-3. This is consistent with the idea that these three factors, which have all been moving in the wrong direction in the last 40 years, contribute to NAFLD.


* Fatty liver was assessed by liver enzymes, admittedly not a perfect test. However, elevated liver enzymes do correlate fairly well with NAFLD.

** Steps I and II were replaced by new diet advice in 2000. The AHA now recommends keeping saturated fat below 7% of calories.  However, the new recommendations focus mostly on eating real food rather than avoiding saturated fat and cholesterol.