Saturday, April 26, 2008

Lipoprotein(a) and genetics

There's a diagram of the structure of human Lp(a) here. The apolipoprotein(a) molecule is the curvy bit partly wrapped around the lipid particle. The section which varies on a genetic basis is the number of repeats of the kringle IV type 2 (shown in black). There can be as few as 10 repeats or more than 50. The rule of thumb, within a given population, is that the lower the number of repeats there are, the higher your total plasma Lp(a) is likely to be. NB comparisons between populations are notoriously difficult. Better control your variables and stick to one population.

It almost looks as if the liver wants a certain number kringle IV repeats in the circulation. If there aren't many kringle IVs in the gene, the liver puts more whole protein molecules out to get the number up. Each protein is attached to a single LDL cholesterol particle. Short repeats mean more individual apo(a) proteins are needed to get the number up, which means a higher Lp(a) concentration. It's not a complete equalisation of kringle IV repeats, but that's the general organisation.

The vegetarian Bantu have two things which are special about their Lp(a).

The first is that, despite considerable intermarriage with fishing Bantu, they are genetically short on the kringle IV repeat front so, naturally, they produce more apo(a), attach each to an LDL, so have higher Lp(a) levels across the board compared to their more carnivorous cousins.

The second is that, if you control for this effect by selecting and comparing two genetically apo(a) matched groups, one veggie and the other fish eating, the difference decreases but is still significant.

What can you make of this? The first thing must be that there is a selection pressure to maintain the differences in apo(a) genetics. Either the fishermen don't need much Lp(a) or the vegetarians need lots. I think the vegetarian environment is such that people with high Lp(a) are more likely to survive.

Second follow on is that the extra Lp(a) from the genetics of the vegetarians is not enough. There is some scope for "pushing" Lp(a) levels up or down from the level you might expect from the genetics of apo(a). The vegetarian environment requires higher Lp(a) than the fishing environment.

We know from intervention studies such as DELTA that a simple change of 7% of calories in the SAD from saturated fat to carbohydrate will increase Lp(a) levels by 20%. What does this mean?

If you subscribe to the "Lp(a) is a suicide lipoprotein" theory, you have to conclude that replacing saturated fat with carbohydrate makes your liver want you dead, by 20% more than it did when you ate butter.

Using monounsaturates instead of saturated fats is not quite as bad, the hepatic homicide lipoprotein only goes up by 11%.

The other way of looking at the changes is to suggest that your liver either monitors your macronutrient intake (you think it doesn't?) or some marker of vascular damage. If you do something which is either is outright damaging, or which is sensed as potentially damaging, your liver acts to save your life. If it "perceives" that you need more Lp(a), you get it.

What each of us gets in terms of the genetic number of kringle IV repeats is probably determined by where our personal ancestors lived. Not much we can do about that. What ever we do to tweak this background level of Lp(a) production is up to us.

From the DELTA study it's pretty clear that no one is going to drop their Lp(a) by eating "healthy" monounsaturates or carbohydrate. From the fish oil study we can see that you won't get any joy from adding omega 3 fatty acids either. I've not seen the effect of omega 6s on Lp(a), but I'd guess they're probably as bad as carbohydrate.

As I see it Lp(a) is a very interesting lipid. I think it's hard to get much information from a single measurement in isolation, but changes in Lp(a) probably give you marks out of 10 for your changes in food choices. "Healthy" oils and carbohydrate score you zero. These are likely to damage your vascular system as judged by your liver's increased output of Lp(a). A surrogate for vascular damage would be the increasing blood pressure with age seen in the vegetarian Bantu, probably related to their 82% carbohydrate diet, and so they will need more Lp(a). They get it.

Down at 70% carbs the fish eating Bantu cope well and don't have degenerating arteries to raise their blood pressure, so they don't need so much Lp(a). They don't make it.

I'd predict that substituting beef dripping for both carbohydrate and olive oil would give you the lowest Lp(a) concentration within your genetic window.


Wednesday, April 23, 2008

PCOS and LC; is pregnancy a side effect?

This review dropped out of Pubcrawler today. How to get pregnant if you have PCOS.

"Fat should be restricted to < or =30% of total calories with a low proportion of saturated fat"

Of course it must, what else would you expect? Now here's the real giggle:

"High intake of low GI carbohydrate contributes to dyslipidaemia and weight gain and also stimulates hunger and carbohydrate craving"

I'm sure it does, but who would have expected the low fat brigade to realise this? I can't get the full text to see if this is a typo (it MUST be!), but if not, you can't eat fat and you can't eat low GI carbs. Sounds like sugar on your veggie burger is all that's left! The abstract gives no indication of how likely you are to conceive if you follow this advice. I don't think I'd trust it as a form of contraception but...

Of course you could always try living within the limits of your insulin resistance, but (gasp) you might have to eat >30% of calories from fat. This was a pilot study. Only five of the eleven women completed the 24 weeks on the diet. Which diet?

"They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks"


"Two women [out of five] became pregnant despite previous infertility problems"

For anyone who might not want to get pregnant, you do have to do something more than eat LC for pregnancy to happen... and be female!


Lipoprotein(a), a prickly subject

Convergent evolution is a fascinating subject. Lipoprotein(a) has been independently evolved at least twice, not only to produce a remarkably similar (but not identical) molecule each time, but on both occasions it has been by a modification of the same gene, that for plasminogen. The two groups with well characterised Lp(a) are of course old world primates (including man) and the hedgehog. You thought the non primate was the guinea pig? Well, I've not been able to find any replication of Pauling and Rath's work with lipoprotein(a) in guinea pigs and the people who did the work with hedgehogs have looked for the apoprotein(a) gene in guinea pigs, pretty thoroughly... and without success.

What is lipoprotein(a)? It's perhaps best described as a super LDL. Just imagine taking a lethal LDL particle and wrapping it up in a second protein, apo(a), which is not only specifically designed to bind the whole lipid particle to the fibrin present in a blood clot, but which also inhibits clot dissolution. On top of that (could it get worse?) apo(a) is heavily and specifically glycosylated with a sticky sugar coating which will bind to the arterial wall. Hmmmm, if you wanted to clog an artery with lipid, this has got to be your glue!

A quick trip to St Tiggywinkles Hedgehog Hospital would be expected to reveal cages of recuperating hedgehogs, victims of strokes, aortic aneurisms, heart attacks, peripheral vascular disease, all of the problems associated with elevated Lp(a) in humans. In truth my guess is that most of them (the hedgepigs) will actually be victims of road traffic accidents, lung worm infection (a killer in hedgehogs) and late summer birthed toddlers who won't overwinter successfully in the wild.

Perhaps Lp(a) in hedgehogs is different to Lp(a) in humans. It has certain structural differences, but it still acts in as an inhibitor of clot dissolution in models based on human tissue. The fact that it doesn't seem to cause vascular problems in hedgehogs is all the more surprising when you realise that it is THE bulk lipid transport particle in hedgehogs!

The other very strange thing about Lp(a) is that it tends to be rather good for you if you (as a human) make old bones:

"lipoprotein(a) elevation in centenarians, in the absence of other coronary artery disease risk factors, appears as a positive survival factor"

It's worth noting that many of the risk factors for heart disease are turned on their head anyway in the elderly, once you look at all cause mortality. If you are over 65 years old, white or African-American then better think twice about popping that statin! You might end up in that lowest quartile of LDL cholesterol, maybe down at 60mg/dl:

"hispanics had the best overall survival, followed by African-Americans and Whites. Whites and African-Americans in the lowest quartiles of total cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) were approximately twice as likely to die as those in the highest quartile"

Just to simplify, low LDL cholesterol=death. That got missed out of the conclusion line! For hispanics, all lipids were irrelevant once you cracked 65 years of age, ie high LDL is not protective in elderly hispanics, nor is it a problem. Of course this is only New York, things may be different in other places. Maybe.

Well, that got me side tracked. Back track with Lp(a) next post.


Tuesday, April 15, 2008

Kwasniewski and cancer

Some problems are more difficult to influence than others. I have this mental image of nutrition as comparable to having your car serviced. Treat your car with respect and you will have to be unlucky for it to break down. If you ignore servicing, say you never top up the brake fluid, eventually the brakes will fail. If you end up writing the car off, say by being unable to stop at a roundabout, there is no point going back to the wreck, pouring some brake fluid in to the master cylinder and expecting the car to become functional again. It won't.

Some people get broken, I suppose all of us do eventually. But it seems improbable that diet could reverse the degree of "broken-ness" represented by cancer, one of the most serious of metabolic train wrecks. But there are reports of remission. Spontaneous remission is one thing. Engineering that spontaneity is quite another.

Can it be done?

Kasha Mikoda has left a comment on the Praise the Lard post. It's a personal account of the management of her father's non-small cell carcinoma of the lung, with mets. By Kwasniewski. It's there for the reading. Non-small cell cancer includes squamous cell, large cell and adenocarcinoma, prognosis guarded.

Her comment brought to mind an old article I read some time ago about the nutritional management of lung cancer, here.

And of course there are always the two children described by Nebeling.

In terms of an evidence base, case reports in peer reviewed publications carry little weight and non published case reports are just off the radar. But then getting a prospective trial set up to provide an evidence base, even a pilot study, is fraught with difficulties. For a flavour of the current state of difficulty anyone can browse the article which started Kasha off on her journey to Kwasniewski. Attempts at collaboration with mainstream medicine by Kwasniewski never got off the ground.

After that there is patient compliance! Look at this quote from Dr Schmidt in the article cited by Kasha:

Four of the patients were so ill, they died within the first week of the study. Others, says Schmidt, dropped out because they found it hard to stick to the no-sweets diet: "We didn't expect this to be such a big problem, but a considerable number of patients left the study because they were unable or unwilling to renounce soft drinks, chocolate and so on."

Of course these people were end stage and probably considered themselves beyond hope, so why not enjoy whatever food they could manage... But for the life of me I can't see why one has to be absolutely at the end stage of cancer before it is considered ethical to advise that you should stop eating sweets, especially when a PET scan confirms that the cancer lights up like a... Well, like a cancer feasting on glucose in a PET scanner.


Monday, April 14, 2008

Metabolism; mitochondria and uncoupling

Just a final couple of aspects of Nick Lane's ideas about mitochondria, diet and aging before I finally leave them alone. There are some factors which he suggests might be associated with longevity.

The first is high numbers of mitochondria per unit basal metabolism. This is the approach taken by birds and bats (which live far longer than similar sized non flight mammals). The metabolic rate needed for flight is such that resting metabolic rate can be met by the copious mitochondria running at tickover. This is effective at supplying energy without free radical leakage, especially with factor two taken on board. I don't think we'll ever get near to bird numbers of mitochondria, but upping the numbers doesn't seem like a bad idea. How about a few ketones to help?

The second is uncoupling proteins. These allow the hydrogen ion gradient in the mitochondria to be dissipated as heat. This in turn allows through flow of electrons down the electron transport chain, even if there are buckets of unused ATP hanging around. Through flow without obstruction means minimal sewer leakage, less free radicals, less apoptosis...

From this abstract, note that:

"Fatty acids are known to enhance mitochondrial uncoupling protein (UCP) activity"

No mention of glucose doing this! The point of the paper is that ketones do exactly the same thing. I don't see the need for frank ketonuria, but I do like to have ketones on tap for whenever they might be needed!


Sunday, April 13, 2008

Cynthia Kenyon link

Here is a link to an interview with Cynthia Kenyon, published in New Scientitst back in 2003. It's subscription only now and though I've got a copy on my hard drive it might be better if I just direct you to a site where someone called James Hughes will provide the text!

She is heavily committed to finding a life extending drug. To me, personally, this will run smack bang in to the Law of Unintended Consequences head on. Lowering insulin by diet choices, as she currently practices, seems to be the best plan for a reduction in the diseases old age. (Peter crosses fingers).


Tuesday, April 08, 2008

Cholesterol, MESA and EBCT

Thanks to Dave Lull for a copy of the latest MESA paper. I guess you could just say EBCT looks like a good predictor of heart attack risk, irrespective of age or ethnicity and leave it at that. It looks to be true.

I was just browsing through table one of the results and a few strange things came out. First is that it doesn't include LDL cholesterol at baseline! Most people with any shred of intelligence will realise that calculated LDL cholesterol is garbage, but it's not typical of the average cardiologist to get that far.... These guys must be good!

The second gem was that HDL was lower in the coronary event group, as happens in Framingham. But the difference between the means was 51.0 minus 47.3, I make that 3.7mg/dl. The standard deviation was 15 ish in both groups. If they had a Normal Distribution, which they should have, the range to include most participants is about three standard deviations around the mean. The overlap is phenomenal between heart attack and non heart attack groups. On a personal basis having an HDL of 20 could easily put you in either group, as could an HDL of 60. I guess cardiologists just get used to this.

Taking lipid lowering medication appears to be as bad as being a current of former smoker. Must be a message there but I can't work it out...

Anyone tempted to crash diet might be disappointed by the BMI in the coronary event group being .2 units lower than the spared group. Good job this has neither biological or statistical significance, or participants might have to be encouraged to gain a few pounds. Or get shorter!

I know all of these things need to be factored in to correct for know interactions as it's likely that all of the diabetics were on statins while being encouraged to eat healthy starches and shoot up with insulin, but the raw data still give me a chuckle.

So Detrano et al provide more evidence that coronary calcium, the physical evidence of on going disease, is a better marker of a physical on going disease process than a surrogate of any sort. They also seem less wedded to conventional risk factors. But I guess that's why they're doing the study...


Gluten and cardiomyopathy

Again, just a brief note. You want cardiomyopathy? Eat your healthy whole grains and start saving for that heart transplant! Or crossing your fingers if you're in the NHS.

Bear in mind that antibody production is far from necessary for gluten damage, so there is no reason why the two antibody negative patients might not have gluten related damage. Also many "non" coeliac people could equally have gluten damage without gut signs.


Metabolism nuts and bolts

Nick Lane has produced an interesting book in Power, Sex, Suicide. When it gets down to basics, the electron transport chain of the mitochondria is a bit like a cracked sewage pipe. If that supplies all the information you wanted to know about aging, stop reading now.

What he means is that it leaks unpleasant stuff but usually only in small amounts unless there is a blockage, which fills the pipe and increases leakage pressure. Otherwise just a little of the nasty stuff escapes.

Just to leave sewer analogies aside for a while, what is the electron transport chain? It's a set of very complex molecular structures embedded in the innermost membrane of the mitochondria. It takes an electron (from where, later) and passes it through a series of "mills" and "conduits" until eventually it off loads it on to an oxygen molecule (this is why we breathe, oxygen isn't needed for much else). As it goes through the "mills" its energy is used to pump hydrogen ions from the innermost recesses of the mitochondria in to the outer zones. The more electrons through the mill, the more pumping. The hydrogen ions want to get back in. The only route back in is through a turnstyle. As the turnstyle turns, rotated by a returning hydrogen ion, a mechanism pushes an extra phosphate group on to an ADP molecule to form an ATP molecule. ATP is exported and used as the energy currency of the cell. Most, but not all, ATP is made this way. There are other routes back for hydrogen ions too, but that's another story.

Back to the sewer metaphor. The electron transfer chain leaks. It leaks raw electrons. Electrons react with anything and everything. Many things affect the rate of leakage and the consequences of leakage, but ultimately the knock on effect of this is damage to the mitochondrial DNA, which codes for certain essential components of the electron transport chain... As the DNA degrades over the years the electron chain components become more leaky and more damage is done and we age.

So much comes from PSS. There are very detailed and mostly convincing arguments for this view of aging and a number of other aspects of Life the Universe and Everything. The answer does not appear to be 42.

That got me thinking. Back to Moseby's Crash Course in Metabolism and Nutrition. A quick comparison of the break down of glucose and palmitic acid comes out with this: Glucose goes through glycolysis to pyruvate. Pyruvate enters the mitochondria, gets converted to acetyl CoA and drops in to the ubiquitous tricarboxylic acid cycle (unless your metabolism is VERY strange, like H. pylori). Palmitic acid, my favourite calorie source, gets an executive ticket straight in to the mitochondria where it undergoes beta oxidation to acetyl CoA and after that it could have been sugar (ie acetyl CoA from any source goes down the same cyclical plug hole).

So the difference in metabolism is between glycolysis and beta oxidation. These provide electrons for the electron sewer in different forms. You can't shift electrons around "neat" unless you are using some copper wire or the like. Neat electrons are what do all of the damage. No, electrons are shifted about as chemical electron equivalents. One is NADH, the other is FADH2. Doesn't matter what these stand for. Converting glucose to Acetyl CoA provides a little NADH and that's it. Converting palmitic acid to acetyl CoA provides a whole load of "electrons", in the form of an equal amount of NADH and FADH2. After that it's all acetyl CoA and the same as glucose. But for every calorie of glucose you burn, you generate a higher proportion of NADH to FADH2 than by burning palmitic acid. So what?

NADH puts its electron in to the start of the electron transport chain at complex I. Complex I is leaky. FADH2 puts its pair of electrons in to complex II, which isn't. There is some leakage at complexes III and IV, but complex I one is the worst and fatty acids partially bypass it. I'd like to keep my mitochondria as happy as possible, as they decide when my cells are going to age and die. The later the better. Minimising leakage seems like a good idea (although some is necessary for health, read PSS).

The biochemistry suggests that running your metabolism on fat may release less free radicals than running it on glucose. As I am hopelessly biased in favour of fat metabolism and I enjoy the nuts and bolts of biochemistry, this makes me happy.

It also puts some logic and a mechanism on to Cynthia Kenyon's comment (in reply to being asked why she restricts her carbohydrate intake, ie is it to extend her life expectancy):

"That's not necessarily why I do it. I do it because it makes me feel great and keeps me slender. And I don't feel really tired after a meal. But I think if I wanted to eat in a way that extended lifespan this is how I would do it. In fact, I stopped eating carbohydrates the day we found that putting sugar on the worms' food shortened their lifespans."

I know what she means about feeling good and staying awake after a meal.

Personally I think old age is a not the problem, it's getting there without those diseases normally associated with it that would be nice. If you can become aged and stay disease free, the longer it goes on for the better.


Tuesday, April 01, 2008

Athletic acid reflux

If you work on the basis that gastroesophageal reflux is carbohydrate poisoning, you would expect a LC diet to provide remission of symptoms. Just reading through the abstract of this paper from g, that would appear to be the case. Six days is a pretty short period to sort our GERD and no doubt there would be further improvement with time. The other tweak would be gluten elimination, not that much would be coming through at 20g of carbs per day.

This goes nicely back-to-back with another paper which has been lying around on my hard drive for some time. There is a fairly large literature as to why exercise results in an omprazole deficiency in athletes, with lots of ideas floated around about pressure changes, hormones etc. I think it's reasonable to describe many endurance athletes, the ones worst affected, as indulging in "carb loading". Apart from furring up their coronary arteries with sugar, GERD would seem be (yet) another price that must be paid by athletes for this practice. I'm glad so say that I have no personal experience of GERD, though my wife could write a book bout it.


BTW Nice to see Grete Waitz doing well.

Fiber, sucrose and ulcers

Thanks to g for this paper. It's a little observational study looking sucrose vs fiber and their possible association with peptic ulcer. Cleave suggested refined carbohydrate caused duodenal ulcers. The carbophillic nature of post-Keys medicine suggested that fiber could redeem carbohydrate as a source of nutrition. This group from Nottingham (my place of origin) appear to be dubious about this. This phrase comes from the discussion:

"Despite the current healthy diet lobby there were no claims of increased (or decreased) fibre intake by patients or control subjects"

The clear association of ulcers with sucrose was interesting. The total lack of protection from cereal fiber was too (sorry, lack of negative association). But the best bit was vegetable fiber. This was slightly "protective". Until you corrected for social class (and a few other things), at which point the association was lost. Looks a bit suggestive that vegetable fiber intake might just be a surrogate for being more well off.

Another throw away comment from Nottingham in the late 1980s was that Crohn's disease is consistently associated with high refined sugar intake. I think I've seen quite a number of studies coming to that conclusion. But surely sucrose (or HFCS for that matter) can form part of a healthy balanced diet...