Tuesday, January 13, 2009

The Total-to-HDL Cholesterol Ratio -- What Does It Mean?

by Chris Masterjohn

Someone recently forwarded to me two references that a high-level New Zealand professor had used to support recommendations against saturated fat and coconut oil. The references did not support the conclusion at all, but they did provide some interesting insight about the importance of the total-to-HDL cholesterol ratio and its dietary implications.


Both of the studies referenced were meta-analsyses. These are studies that pool together the individual data points from many other individual studies. The drawback is that often times the individual studies will have used different methods or definitions or some will have been of poorer quality than others. Both of these meta-analyses, however, appear to be well done and to have used sound criteria for inclusion. The benefits are that they give a sense of the totality of the evidence and that they are statistically much more powerful because they have such a dramatically larger sample size.


The Importance of the Total-to-HDL Cholesterol Ratio

The first study was a meta-analysis of 61 prospective studies published in 2007 that included almost 900,000 people followed for an average of over 13 years and over 55,000 deaths from cardiovascular diseases. It found that total cholesterol was the worst predictor of heart disease mortality risk while the total-to-HDL cholesterol ratio, which is essentially the same thing as the LDL-to-HDL cholesterol ratio since most non-HDL cholesterol is LDL cholesterol, was the best predictor.

In both men and women, a 1 mmol/L (just under 39 mg/dL) lower ratio was associated with half the risk of heart disease mortality in those aged 40-49 years, two thirds the risk in those aged 50-69 years, and five sixths the risk in those aged 70-89 years.

The first thing we can observe is that while the importance of the ratio diminishes as people grow older, it is still statistically significant in a massive meta-analysis. This shows that when studies find blood lipid levels are not risk factors in old age, they are confusing statistical significance with clinical significance -- the ratio is meaningful, but the smaller magnitude just isn't detected in studies with lower statistical power.

Why does the risk decline with age? First, let's consider what the total-to-HDL cholesterol ratio even means. The fact that it is associated with heart disease risk does not mean it causes heart disease risk. But it could.

As described in my article, Cholesterol and Heart Disease: Myth or Truth?, the initiating factor in atherosclerosis is the oxidation (or glycation) of LDL particles in the blood. In the later stages, oxidized LDL also contributes to the inflammatory action of the foam cells it finds itself stuffed in, but these cells also recruit T cells that make their own inflammatory contribution independent of oxidized LDL, so its importance declines. Oxidized LDL contributes to plaque rupture, but so do other inflammatory factors as well as deficiencies of collagen production, which are probably influenced by vitamin C status. Thus, oxidized LDL is central to the initiation of the disease, but as the disease progresses the contribution of oxidized LDL is diminished.

Where does HDL fit in? Much has been made of its role in reverse cholesterol transport, but that has little to do with the oxidation of LDL or the oxidized derivatives of linoleic acid that have been shown to turn on the "foam cell" genes in the monocytes that first swallow them up. As described in the article I linked to above, when the contribution of oxidized LDL was first discovered in the late 1970s and early 1980s, researchers found that HDL or vitamin E both prevented the oxidation that would occur when LDL was exposed to the cells that line the blood vessels for a prolonged period of time. As I have pointed out on my site elsewhere, HDL is responsible for delivering vitamin E to these cells.

So that suggests a protective, causal effect of HDL, but not HDL cholesterol. And in fact, interventions to try to specifically boost HDL cholesterol have not been terribly successful. The most notorious case was torcetrapib, a drug that was designed to block the transfer of cholesterol from HDL particles to LDL particles. Not only was it toxic, but a recent trial concluded the following:


The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection.
In other words, keeping the level of cholesterol in the HDL particles high does not reduce the progression of atherosclerosis. This suggests that while HDL protects against atherosclerosis by preventing the oxidation of LDL, HDL cholesterol does not protect against atherosclerosis by transporting cholesterol away from peripheral tissues and back to the liver. This is unsurprising, considering it is the oxidation of LDL and not the transport of cholesterol to peripheral tissues that contributes to atherosclerosis.

So what would the total-to-HDL cholesterol mean? The longer LDL stays in the blood, the more two things happen: it is exposed to oxidants, and as its limited supply of antioxidants run out, the polyunsaturated fatty acids in its membrane oxidize, leading to the further oxidation of its proteins and cholesterol; it is exposed to cholesterol ester transfer protein (CETP), which transfers cholesterol from HDL to LDL, thus boosting the total-to-HDL cholesterol ratio.

So the total-to-HDL cholesterol ratio should be a marker for the amount of time LDL particles spend in the blood. This, in turn, is dictated by the activity of the LDL receptor, which brings LDL into the liver and other tissues that need it. Since the liver only packages lipoproteins with a finite amount of antioxidants, it is critical that they reach cells, where antioxidant enzymes are regularly produced, quickly and efficiently. To whatever extent the total-to-HDL cholesterol ratio is high, this probably isn't happening.

How Do Dietary Fats Affect the Total-to-HDL Cholesterol Ratio?

The second study was a meta-analysis published in 2003 of sixty trials testing the effect of feeding different types of fats to humans on the total-to-HDL cholesterol ratio.

The study found that saturated fats did not change the ratio when substituted for carbohydrates. Carbohydrates, however, did raise triglyceride levels and shift LDL to the small, dense pattern associated with atherosclerosis when they were substituted for saturated fats.

Unsaturated fats, especially polyunsaturated fats, decreased the ratio. But so did specific saturated fats like stearic and lauric acids. "As a result," the authors wrote, "lauric acid had a more favorable effect on total:HDL cholesterol than any other fatty acid, either saturated or unsaturated."

They pointed out further that even highly saturated fats like dairy and tropical oils contain some unsaturated fat, so they will all decrease the ratio relative to carbohydrate. And since coconut oil is rich in lauric acid, it would be especially effective in reducing the ratio.

In contrast to all of these fats, trans fats raised the ratio.

What Does This Tell Us About Dietary Fat?

Before we conclude anything about what type of fat we should eat, we must remember that correlation does not prove causation. As I pointed out above, evidence suggests that the total-to-HDL cholesterol ratio is a marker for the time LDL spends in the blood rather than a causal factor itself. So we cannot conclude that PUFA oils and coconut oils are the best fats to prevent heart disease based on this meta-analysis by itself.

The latest edition of the widely respected textbook Modern Nutrition in Health and Disease states that linoleic acid (a PUFA found abundantly in vegetable oils) decreases cholesterol levels because the enzymes that store cholesterol by connecting it to fatty acids, called esterification, will selectively use linoleic acid. Thus, while liver cells get stuffed with cholesterol linoleate esters, their level of free cholesterol declines and they produce more LDL receptors on their surface, which bring LDL in from the blood.

Increased expression of the LDL receptor is good. But this meta-analysis considered blood lipids to reach a steady state by 13 days. Maybe cholesterol linoleate can accumulate in the liver for 13 days without adverse effects, but what happens over the long term when cholesterol esters progressively accumulate in that organ? Can that go on forever? Longer studies would be needed to find out.

It isn't quite clear how some saturated fats decrease the total-to-LDL cholesterol ratio. Perhaps they enhance LDL receptor function by decreasing oxidative stress, but there could be many possibilities.

As the authors of this meta-analysis pointed out, we should rely on controlled trials testing the effects of dietary fats on heart disease risk rather than extrapolating from surrogate markers. They cite several trials showing that unsaturated fats reduce heart disease risk compared to saturated fats.

These trials, however, were often poorly conducted or deceptively interpreted. Moreover, a number of trials showed the opposite, like the Rose, et al. (1965) trial that found corn oil to quadruple the risk of heart disease when substituted for butter over the course of two years. I have discussed those trials here.



Read more about the author, Chris Masterjohn, PhD, here.



35 comments:

  1. Chris,

    I like your theory about the TC:HDL ratio reflecting the amount of time LDL remains in the blood.

    Also, what you said about the liver saturating with linoleic acid makes sense. I've written a number of times about non-alcoholic fatty liver disease on my blog. You can induce it readily in rats by feeding them a high-linoleic acid diet but not a high-saturated fat diet. Large amounts of fructose also does the trick.

    Since I suspect liver dysfunction is central to overall metabolic dysfunction (after all, the blood tests you get at the doctor's office like fasting glucose, insulin, cholesterol, partly reflect liver function), I think LA could be a central and long-term mediator of metabolic damage by that mechanism. Fish oil protects against NAFLD in rats.

    NAFLD affects 20-30% of people in industrial countries, and the more serious non-alcoholic steatohepatitis a substantial fraction of those. A few decades ago, the only reason you got steatohepatitis was alcohol.

    I suspect MetSyn goes something like this: too much LA plus fructose turns your liver into foie gras, after which it can't properly clear insulin and glucose, produces excessive glucose because it's insulin resistant, can't secrete or uptake lipoproteins correctly, etc. Once insulin sensitivity in your liver is gone, you can kiss your whole-body insulin sensitivity goodbye. The liver-specific insulin receptor knockout mouse (LIRKO) is a mess. One of my favorite models of metabolic syndrome.

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  2. Stephan,

    Thanks for your comments. The same is true for the alcoholic model. Rats on 40% corn oil develop fatty liver in response to nearly 30% of calories as alcohol, but rats on 40% of cocoa butter do not develop fatty liver on nearly 30% of calories as alcohol. A mix of MCT oil and tallow has a dose-dependent protective effect when it is progressively substituted for more and more of a 40% corn oil diet.

    What was the control in the fish oil study? Did it substitute for carbohydrate, saturated fat, or n-6 PUFA?

    Chris

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  3. Chris,

    Here's the study. I misquoted it, it was done in humans. Bu if I recall, it was a follow-up to experiments in rats that showed the same thing. I haven't looked into it in detail so I can't vouch for the quality of these studies. This one doesn't look placebo-controlled but the results are quite robust:

    www.ncbi.nlm.nih.gov/pubmed/16611275

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  4. Hi Chris!

    I'm glad you discussed the failed Torcetrapib trial. A balance of CETP reduction and PTLP accentuation are necessary for optimal lipoproteins and disease protection.

    Right? :)

    http://drbganimalpharm.blogspot.com/2008/10/saturated-fats-as-potent-anti.html

    Thank you for all your Wise Tradition entries -- they've provided me a great foundation of nutritional science info! I've read nearly all of them...

    If you get a chance, I'd love to see a review of the stats and literature on vitamin A protecting against vitamin D toxicity (and vice versa). I recall from one of your Wise Tradition articles, one citation from a PhD dissertion defended how vitamin A protected against toxicity from D. Is there new data?

    Take care,
    G

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  5. " a 1 mmol/L (just under 39 mg/dL) lower ratio was associated with half the risk of heart disease mortality"

    The article says that
    "mmol/L lower total cholesterol was associated with about a half.."

    Ratios don't have units...

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  6. Chris,

    I recently received some curious results on my blood panels and am curious for your feedback. I am sorry to trouble you with my personal story but am not sure where else to go for info. I appreciate any help you can provide, in addition to what you have already done with this blog, which is a terrific resource.

    In May 2007 my blood panel looked like this:

    Total cholesterol 155
    Trigylcerides 65
    HDL 50
    LDL (calc) 92

    In Jan 2009 I received the following:

    Total cholesterol 311!
    Trigylcerides 43
    HDL 88
    LDL (calc) 214!

    I am currently 41, athletic, do high intensity short duration exercise 3-4 times/wk, low body fat, fairly good health. I changed my diet in Jan 2008 from a standard "healthy" diet to paleo style after reading Cordain's book. I followed Cordain's recommendations fairly closely for about six months, eating lots of fruits and veggies, lean meat (trimming the fat), very few starches, and nuts seeds avocados, olive oil, etc. In summer I began reading some blogs and books which recommended a diet higher in sat fats, lower in protein and lower in PUFAs, so I made some changes by severely limiting PUFAs (no more nuts, less fatty chicken and pork) and eating fattier red meat, coconut oil. I also cut down on veggies and fruits and added starches and white rice. More of a WAPF style or Optimal Diet.

    While I would consider myself a cholesterol "skeptic", I am by no means an expert and was amazed by the increase in cholesterol and am very curious what this means and why. I understand that some of the numbers here (e.g. total cholesterol) don't mean much, that some of the numbers (e.g. hdl/tris ratio) are good, that LDL calc is often inaccurate, and that based on my low tris, my LDL is likely to be large and fluffy instead of small and dense. But I am still amazed by the rise and curious what it means. Should I be concerned? Why did this happen so fast? Thanks again for any guidance you can provide.

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  7. I'm so sorry I missed these comments!

    Dr. BG,

    I have reviewed the protective effect of vitamin A against vitamin D toxicity in more detail in From Seafood to Sunshine and in Vitamin D Toxicity Redefined, which is published in Medical Hypotheses. You could follow up the references therein.

    Quelle, thank you for the correction!

    Frederick, your TG are low. Check this out:

    http://tinyurl.com/cv5yd8

    When TG were low (55), LDL (calc) overestimated the actual LDL-C level at 172 when it was really 126.

    Total-to-HDL cholesterol ratio is still high. I'm not sure if it's a concern -- it's high in the Kitavans, and they apparently don't have heart disease. In most populations, it's a marker for heart disease risk. In your case, maybe the coconut oil is ramping up cholesterol production but you aren't necessarily having a problem clearing LDL. Coconut really throws the whole "marker" issue out of whack because it increases the energy state of the cell, which increases cholesterol synthesis. It's LDL clearance that matters, not cholesterol output from liver into blood. Other aspects of health need to be taken into account. Has your general health improved or worsened or stayed the same?

    Chris

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  8. Frederick,

    One more point. You should get your apoB and apoA levels checked. The important issue here is LDL clearance. If your ApoB is normal and your LDL-cholesterol is high, this suggests that not only are the particles large (good), but that you have simply increased the cholesterol-to-TG ratio of these lipoproteins by eating low-carb (reduces TG synthesis) with lots of coconut fat (increases cholesterol synthesis), while you are clearing the lipoproteins at a normal rate. That would be a fine thing not to worry about. If your ApoB is high, I'd be concerned.

    Chris

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  9. Chris,

    Last week I had been to lab work and the results are this:

    HDL: 39
    Triglycerides:75
    Total Cholesterol: 134
    LDL Calc: 79
    HbA1c: 5.0

    I am a Type II Diabetic Male 38 years, on a Low carb (<40g netcarbs per day) diet since June 2008.

    Dr is asking me to take Niaspan and I do not want to take any tablets unless it is necessary. I do not take any pills for any purpose other than Fish Oil capsules for Omega 3 supplements (once a day).

    Please suggest if there is way to increase my HDL through diet/exercise method.

    I go to Gym and do weight training 45 mins 4 times a week and 15 min in ellipticals 4 times a week.

    Thanks for your time.

    Venkat

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  10. Venkat,

    Replacing your other fats and oils with coconut oil will likely help. Additionally, in about 30% of people 3-4 eggs per day will raise HDL-C (in the others it does nothing; it will also raise LDL-C but your LDL-C is low).

    Chris

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  11. Chris,

    Thanks for the advice. I have been consuming 2 eggs per day for the past 6 months. During last week blood work results - Uric acid increased from 5.9 to 8.0. (and 8.0 in the upper limit).

    I did not take coconut oil at all in the past. I will certainly give that a shot.

    Thanks

    Venkat

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  12. Chris,

    Awesome work as always from you. I have a question on my current status. Very worried about my recent lab work I got back. I've been on a full 100% organic diet for the past 3 months - grass finished beef, completely organic eggs, raw dairy, and organic fruits/veggies. I take about 1 tbsp of coconut oil a day in the morning. Run 2-3 days a week, lift for 45 minutes/3 days a week. My levels were not what I expected to be honest:

    274 - Total C
    195 - LDL C
    40 - HDL C
    196 - Triglycerides
    2952 - LDL Particle Size
    2191 - LDL Small Particle Size

    Any tips or things I can do naturally. I am very very very apprehensive about using statin drugs. Thanks and I will keep on reading your work Chris!

    GC

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  13. This post is very informative. It is also helpful for the readers. Thanks for sharing this topic about HDL Cholesterol Ratio. God bless you!

    http://feelbettercenter.com/

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  14. I know this thread is quite old, but I really wanted to jump in here...

    First of all, fantastic article Chris. From everything I have read, at this point I consider you to be pretty much the leading authority on the topic of cholesterol. But I do track with Chris Kresser and Stephan G very often as well. The three of you are my favorite sources for sound info about health.

    Okay okay sorry about the brown-nosing.

    "Fredrick's" numbers (above) seem fantastic to me. Double HDL to Trig ratio. 88 HDL to 214 LDL sounds fine, especially since it's "calc" like you mentioned already. In fact, I envy these numbers. I wonder if he ever took up your advice and got his apoB and apoA levels checked. But isn't it almost all but certain that his LDL would be mostly large and non-oxidized since his HDL is so high and trigs so low? Unless there is some sort of Vit E deficiency or something.

    Mine numbers are ok. But then again, I only switched my entire way of eating a few months ago.

    One year ago:
    Total: 208
    HDL: 35
    LDL: 145
    Trigs: 142

    One month ago:
    Total: 270
    HDL: 42
    LDL: 211
    Trigs: 85

    So my HDL increased slightly, but certainly not by much. Also, my trigs plummeted. I believe that would be the result of going low-carb (less than 70/day) for the last 3 months. But my HDL to LDL ratio is not what I'd call fantastic yet. I want to do a full VAP test, which I've never done.

    I eat lots of organic "free roaming" chicken eggs (sometimes fully pastured too). Grass fed beef, wild salmon/fish, raw milk and organic cream, pure cheeses, lots of pasture butter, about a slice a day of Food For Life 100% sprouted grain bread (no white flour/no whole grains), no vegetable oils, Green Pastures Royal Blend, cook in coconut oil and take a tbsp daily (and just ordered red palm oil), and eat plenty of healthy veggies and some choice fruits (no juice). I soak/ferment/prepare anything that needs it including raw nuts for nut butters, and I am fully immersed in all the right blogs and constantly learning more. I also do heavy weight training 3 days a week and drink Whey Cool raw grass fed protein concentrate on those days. I participate in consumerism quite significantly eating this way and I’m fine with that. (In other words, it’s flippin expensive)

    I plan on testing again in 6 months, but should I be concerned about my mediocre HDL of 42 or just wait til next reading after more time on healthier eating?

    Of course… thank you very much for your genius work. It is very much appreciated.

    -Jack

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  15. This study really make sense. Thank you for giving the importance of saturated fat and coconut oil.

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  16. Genius work. Thank you for sharing your insightful thoughts. Thank you for showing both sides.

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  17. This is very useful to anyone who wants to try this one. Very imformative!

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  18. HDL-High density lipoprotein or good cholesterol dimineshes as age gets older...while LDL or low density is bad cholesterol...this report is informative to all ages especially in our society today wherein not all are healthy eaters

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  19. I learned something about Cholesterol Ratio after reading this blog. Thanks for the info!

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  20. It is important to remember that even with a favorable ratio; we have learned that it is still important to try to obtain an LDL of less than 80-100, regardless of the HDL value, especially in the presence of multiple other risk factors for coronary artery disease (genetic predisposition, tobacco use, hypertension, and diabetes). In patients with known coronary artery disease (history of bypass surgery, stents, or PTCA), an LDL of less than 80 is extremely desirable.

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  21. Good post about The Total-to-HDL Cholesterol Ratio. I have learned many things from this post. Great!

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  22. After reading this post, I'll be having my full blood workup. So I will have much better idea of what is going on.

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  23. Very informative post!It gives me more knowledge and idea about cholesterol. Making me aware of my Cardiovascular status.

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  24. Doctor knows best when it comes to our cholesterol goals but its up to us on how to manage and lower bad cholesterols to avoid risk for heart disease. Great content and very helpful information.

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  25. Self-disciple and self-awareness matter most here. But it is a wise decision if we always consult the doctor.

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  26. Thanks for the advice. I have been consuming 2 chicken per day for the past 6 months.

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  27. Reading an article like this is indeed a total package.

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  28. I am asking myself for the New Zealand professor how was he able to defend his lecture if the total references are not reliable. Smart enough!

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  29. How can I LOWER MY TRIGLYSERIDES. And should I take a 'Niacin' w/ pravastatin 40mg. My lab results; TC=234 HDL=33 TRG=276 LDL=146 nonHDL=201 TC/HDL=7.1blood pressure ave.122/82 (w/proprananol10mg)Im open for suggestions. Thanks, Sandcastle

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  30. High triglycerides, if they aren't genetic, are probably caused by insulin resistance and carbohydrate intake. Ultimately, I think normalizing metabolism and being able to eat carbohydrate is best. However, you will probably see TG decline if you restrict carbohydrate. Work on normalizing insulin resistance, and thyroid hormone if it is off, with an physician who is knowledgeable in this area, is my opinion.

    Chris

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  31. This comment has been removed by the author.

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  32. Hello,
    I would like to have your opinion about my lab results. Every year for my physical when labs are run to check my total cholesterol, HDL, LDL and triglycerides my doctor's office calls me to tell me to go on a strict cholesterol diet. Last year my total chol was 239, and I am sorry I don't have the other numbers here. This year the MD just called and total is 242 with LDL 156, HDL 58 and triglycerides 138. My other labs from a year ago are approximately similar. My question is how concerned should I be? When I do the math on the various rations that are important, I do not find myself in a high risk category. This year my doctor wants to repeat my blood work after 4 weeks of seriously curtailing my diet. If no improvement she wants me on a statin drug. I should tell you I am a 55 year old post menopausal woman who takes only one medication for depression. I have no medical problems. My weight is normal and my mother God Bless her is alive and well at 84 with no history of CAD.

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  33. Just got my labs:
    250 cholesterol...yikes!
    140 LDL (yikes!)
    88 HDL (good)
    85 (tris)

    Should I be worried?

    Martta Kelly

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  34. Hello!
    Glad I found this forum, lots of good info here.
    I am a 45yo male, 5.11 and about 190lbs (decent shape). 3 months ago a had a heart attack and a stent put in. Doctor called the problem genetic - twisted artery that eventually got clogged. Cholesterol levels were high at that time - total 341, HDL 26 and LDL 315, Trigl 200. Been taking carvedilol, efffient, 1 325mg aspirin and 40mg lipitor daily since. Changed diet completely, extremely low amounts of sat fat (and fat in general). Lots of fruit and veggie juices (home made). Oct 5 I had another blook work session. Total chol - 111. HDL 45, LDL 66, Trigl - 380!!! Why did they jump like that when I am eating healthy and barely any fat? I also smoked - but cut down from 2 packs / day to 10 ciggs /day and compensate with electronic ciggs.
    Any idea on how to reduce the trigl? Doc wants me to use Gemfibrozil specifically for Trigl, but I already take enough medicine...gonna kill my liver like this.
    Thanks for any response!

    Ted

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  35. just come out of hospital haaving been in for 2 weeks following a right corotid artery dissection and right MCA territry infarction.am now on Warfaruin and simvistatin
    cholesterol is
    total = 247
    ldl=164
    hdl=85
    total and ldl are quite high but tc/hdl = < 3
    and hdl/ldl =0.5 both of which are considered good.
    i am 54 an exercise every day doing an estimated 10mile run each day in the gymmade up of the bike ,treadmill,rower and cross trainer.
    struggling to make sense of all this as seem to have very few of the risks for stroke other than being a bit of a chocoholic but thought the exercise made up for that.
    hopefully i will be allowed back in the gym sooner rather than later

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