Life, Risk & Biomarkers

Let's start out with a little nostalgia, eh?  Before video games, there was a time when humans played boardgames, like Life and Risk.

Newman & Kramer play Risk on the subway!

While life and health is not a war strategy game, we are constantly bombarded with health advice based on observational studies associating risk factors with certain parameters.   From these, we are advised to eat or avoid eating certain foods, acceptable levels of radiation exposure, etc. are determined.

Cardiovascular disease is a huge killer, and for many, a first heart attack is it.  So as sentient beings cognizant of our mortality we'd like to know our risk of dying in this manner and strategies to minimize risks.   But here's a semi-absurd example of this.  Men are at higher risk of dying from CVD than women, but would a sex change operation lower his risk?

When I was 19 I had my first cholesterol test for an employment physical (since I would be working with certain chemicals and such, this unusual process was required.)  The company nurse informed me my cholesterol was on the high end of normal, and offered up the standard dietary advice of the day.  On my next test a couple of years later, I learned my TC was high because I have high HDL.  Pretty much all my life doctors have looked askance at my lipids but mostly I've been spared "the talk" primarily because of the HDL, and because I've only ever been borderline high.  Over the years, my cholesterol levels -- all of them -- seem to track with my weight, not with my diet.

Let's take triglycerides since they are such a poorly understood biomarker.  Everyone agrees that high fasting triglycerides are a risk factor, right?  In the fasted state, triglycerides are pretty much synonymous with VLDL particles produced in the liver.  In Where do triglycerides come from?  Part I, I discussed a radio-label study that looked at the mechanism of carbohydrate-induced increases in fasting triglycerides.  Was it increased de novo lipogenesis (DNL, converting carb to fat), increased VLDL secretion (from esterification of fatty acids from all sources), or decreased clearance of VLDL particles?  The answer, contrary to what "low carb science" tells us, is the latter -- decreased clearance of VLDL.  Here's the graphic of the results using normal men, and those with endogenous (genetics) hypertriglyceridemia.  While the high carb diet changed things slightly for the production of VLDL in normal men, and significantly more for the HTG subjects (the "missing" VLDL is addressed in the other blog post), the elevated fasting trigs were attributable to reduced clearance.

So ... we have a lot of observational studies that show fasting trigs are a significant biomarker for CVD risk.  So let's say my fasting trigs are 100 and I go on a low carb diet and they drop to 50 in a month.  The next month I switch to a traditional carbohydrate heavy Pima diet and my triglycerides soar to 150.  And let's say based on some meta-analysis,  50 puts me in a low risk category, 100 normal, 150 moderate risk of perhaps 20% greater risk of developing CVD.  Heck, forget diet and let's say I had trigs at 150 and took DrugX to drop them to 50, am I healthier?

The triglyceride data include a subset of the population genetically predisposed to HTG, and these people may have a genetic make-up that predisposes them to CVD based on what's causing their higher TG production, or related defect, not the TG themselves.  Carbohydrates don't increase the secretion of VLDL, they slow the clearance.  Now this may or may not be a good thing or a bad thing, but is a "normal" person who's trigs go up on a high carb diet increasing their personal risk of CVD?  After all, their numbers now put them in a different range.  How about the much-vaunted greater reductions in trigs on LC diets?  Now compared to the general population, this puts the same person, with the same genetics and metabolism in a lower risk category.  Or is there anything at all to triglyceride levels in all but this subset that over-produces them?   If you give an HTG person a drug to slow VLDL secretion, are they healthier because their trigs go down?

Given how variable and volatile such lipid profiles can be, and how conflicting various risk analyses are as to the predictive value of this or that biomarker, I personally, would rather rely on whatever measures come down the pike that look for actual physical manifestations of developing CVD, or measure rates of production, clearance, etc., rather than such biomarkers.  Because I don't believe that if my trigs can be changed in a month on a diet, I've altered my risk "overnight" in terms of a lifetime.  And the point of going through the mechanistic stuff above is that I think it is more important to understand why one might have a disturbance in some metabolic process.

Realize that those biomarker ranges are vs. the population as a whole consuming varied diets but some "average" SAD.   If one is to draw any conclusions on their health based on such biomarkers, it would seem prudent to consume an average SAD (doesn't need to be junk food BTW) for at least a month prior.  Then at least you're comparing your Granny Smith apple to all apples.  But every day we hear how this or that biomarker not so good after all.  A email circular landed in my Inbox just the other day questioning the usefulness of ApoB, and there was that study discussed on the news about how endogenous over-producers of HDL (maybe I'm one?) are not "protected" against CVD.

Based on recent studies I've read about the role of glyceroneogenesis regulating esterification in the liver, I think the lowering of trigs with VLC is probably just because glyceroneogenesis competes with gluconeogenesis for substrates.  Glyceroneogenesis is a truncated form of gluconeogenesis, but gluconeogenesis is the more important pathway when push comes to shove.  So in a VLC state your liver is more interested in keeping blood glucose levels high enough than it is in performing its recycling role in the TAG/FA cycle.  You have the same fatty acids circulating around, but fewer esterified into triglycerides due to reduced G3P production in the liver.  Healthier?

Now again, this is my personal opinion, but IMO, lipid profiles are most useful to track for yourself, compared to yourself, on your habitual diet.  If all of a sudden your VLDL starts rising or your HDL dropping or something like that, that would be an indication something's going on.  And I believe they can be informative as to the benefits of dramatic changes in one's diet.  Many people at Paleo Hacks have reported through the roof LDL levels from eating lots of butter and/or coconut oil (ahem Jimmy Moore, your near 400 TC levels are only mysterious to you).  Most people see improvements on LC -- usually associated with weight loss.  But some do not even when losing weight -- were I one of those I'd stay far far away!

In the mean time, while "they" sort out the magical biomarker you can bet the farm on that you'll live a long and healthy life, the best biomarker out there is the mirror and your brain.  A healthy diet shows outwardly though some things take many years to show outward symptoms.  This is where you have to use your brain -- scrubbed clean of all denial -- as to how you feel.   Health and well being shows through your eyes, and I'm not talking about whether or not a person has nice eyes.  And there's that puffiness of inflammation or age-inappropriate emaciation and sagging.  That was the dig against Gillian McKeith but some of the Nigella Lawson pics show the kind of inflammation I'm talking about.  And since Jimmy Moore is fond of posting pictures of others and commenting, it makes him fair game.  My hubs was shocked to learn he was only 40 and he's aged more than 8 years worth if you ask me.  He looks remarkably better in recent pics than on the LC Cruise -- a lot less puffy.  Likely half of his recent weight loss is inflammation-associated water.  His fellow hater of this scumbag hater, OTOH, is the personification of the puffiness I'm talking about.  In just about every picture from the cruise she's got that "look" and you know what I mean.  It's a darned shame because she's a pretty woman (and I'd kill for that hair even as much as I like my own!) and only serious denial has someone proclaiming the healthfulness of how she's eating or trying unsuccessfully to eat.  Many, many of the MDA success stories are improved inflammation with nominal weight loss -- likely because the list of foods to remove from one's diet includes some usual suspects, and that's a good thing.   But demonizing one and now two macronutrients because many problematic factors are associated with some carbohydrate containing foods ... too far by a mile.

 In this game of "pick the biomarker" , I'll go with outward appearances, fully aware that mine fall far short of perfect, and non-denial based general feeling of well-being.  Perhaps it's time for fat biopsies to look for macrophages or crown-like structures, or routine liver screenings or more sophisticated mechanistic tests rather than more sophisticated lipid profiles.   But I think the mirror and our brains are probably the best tools we got. In this game of Life and Risk.