Monday, October 20, 2008

Familial Hypercholesterolaemia; Brown and Goldstein

Brown and Glodstein won the 1985 Nobel Prize for medicine.
You can download their acceptance address as a pdf here.

Their work was primarily based around familial hypercholesterolaemia.

The world is full of genetic problems where the heterozygote, with one copy of an affected gene, has an advantage over people in whom neither copies of the gene is affected. Being a carrier (heterozygote) for sickle cell anaemia protects you from malaria without any disadvantage. Being the far rarer homozygote (both genes affected) is bad news because your haemoglobin polymerises under hypoxic conditions and your red blood cells become dysfunctional. Not nice. Hurts like hell, apparently.

There are lots of types of familial hypercholesterolaemia but I'll stick to the type where the receptor for LDL particles is fully dysfunctional. Get one copy of the gene and you have elevated cholesterol levels but are at no excess risk for CVD, unless you come from a family which has a history of premature CVD. Get two copies of the FH gene and, as for sickle cell disease, you are potentially in trouble. Why is part of a future AGE, RAGE and ALE post, so I'll leave it there for the time being.

Brown and Goldstein came up with a therapy for managing heterozygous familial hypercholesterolaemia.

Heterozygous FH (hFH) people make a lower number of functional LDL receptors because one of their genes for this protein is naff. The other gene is fine. B and G noted that the level of cholesterol within our cells controls the expression of the genes for the LDL receptor. Lower intracellular free cholesterol and you up regulate the LDL receptor gene, to grab extra cholesterol from passing LDL particles. Get enough functional receptors on to cell surface and you behave as if you are normal, LDL-wise.

So they put in place the concept of lowering plasma LDL by up regulating the LDL receptor expression by inhibiting cholesterol synthesis within the cell. You can particularly target the liver by, in addition, depriving it of bile acids. These cholesterol derivatives are fiendishly important and normally get very efficiently recycled. Treating with cholestyramine guarantees, along with gut ache, that most bile acids go down the loo. Now the liver REALLY needs cholesterol (partly to make more bile acids) but also because HMG CoA, the rate controlling enzyme cholesterol synthesis, can be blocked by a mould fungus (eventually to be marketed as lovastatin). So it sticks out lots of LDL receptors and normalises plasma LDL.

And all heart problems disappear. But B and G worked in the 1970s. At that time it had not occurred to anyone that it is only those hFH people with heart disease that get heart disease. The rest are fine. The heart disease cannot be from the elevated LDL, because the non CVD families have similar LDL yet stubbornly have no heart disease. Back in the 1970's no one thought to look for healthy hFH "victims", all of the hFH patients were found through cardiology clinics..........

So the basic principle which was used to usher in lovastatin was based on a mistake. Very clever science, but based on a mistake non the less. Who gave B and G the idea that elevated LDL cholesterol caused heart disease? Who do they cite as the source of elevated cholesterol being the cause of heart disease in their nobel acceptance address?

Well, you can bet it wasn't Yerushalmy and Hilleboe.

Oh, you've never heard of Yerushalmy and Hilleboe? Obviously neither had B and G.

B and G cited Ancel Keys and his seven countries study linking saturated fat to heart disease via elevated cholesterol:

"Extensive epidemiologic studies performed in many populations in many countries over the past three decades have pointed strongly to a general association of high blood cholesterol levels with heart attacks. Among the most striking examples is the seven-country study of coronary artery disease directed by Ansel Keys (116)"

ref 116 is to a text book published in 1980. The original publications were in the 1950s, this one comes from 1953. Unfortunately papers this old are not freely available so I'll personally have trust to Dr Ravnskov to have seen the actual paper based papers.

Yerushalmy and Hilleboe, in 1957, pointed out that Keys had selected his countries to fit his hypothesis and that inclusion of all of the data available at the time showed no association between saturated fat and blood cholesterol, let alone heart disease. Really, that should have been the end of the diet heart hypothesis.

But what is MUCH more interesting (than their believing Ancel Keys) is B and G's opinion about homozygous FH. It was obvious to them that you CANNOT up regulate the effective LDL receptors of homozygous FH patients because they DO NOT HAVE ANY GENES FOR EFFECTIVE LDL RECEPTORS AT ALL. Quote from B and G:

"The principles applied to treatment of FH heterozygotes cannot, unfortunately, be applied to homozygotes, especially those who have totally defective LDL receptor genes. These individuals do not respond to the above-mentioned drugs because they cannot synthesize LDL receptors"

Oh.

So why give statins to homozygous FH patients? Remember, statins are used, in B and G's scenario, to upregulate LDL receptors.

Clearly there is no logic to this.

You could say medicine has been very lucky in the multitude of unsought after beneficial effects from the fungal toxin lovastatin, in addition to it's very unpleasant ability to inhibit HMG CoA reductase and along side a few other rather nasty effects which negate any overall mortality benefit.

Or maybe you could say science has been held back for 25 years by that fluke and that medicine is no closer today to the real causes of heart disease than it was in 1953. Thanks again to Dr Keys.

Peter

19 comments:

brian said...

Nice post. I'd add that McGovern and Carol Tucker Foreman are co-conspirators too.

mtflight said...

Really nice post, Peter. Dumb question: reductase vs. synthetase?

So, it is not uncommon for homozygous FH patients to get statins?

Peter said...

No time for more, got it typowise Alex.

Ta

Peter

mtflight said...

Peter I have the Yerushalmy_Hilleboe paper. E-mail me for a copy "@ gmail.com"

ItsTheWooo said...

I am very interested in FH but don't know much about it. From what I have read, the lack of LDL receptors leads to fatty cholesterol deposits all over the body. This seems to suggest that high LDL does indeed promote plaque formation, but there is individual variation in how sensitive a person may be in forming these plaques. After all, why would outrageous unregulated LDL levels lead to cholesterol plaques on the skin and eyes ...but yet NOT the intima of the vessels in the heart?

Even though there is clearly more to the heart disease story than high cholesterol leading to plaque formation, I think it is just as problematic to dismiss the pathogenic nature of LDL all together... unless I'm wrong, it seems plaques form all over the body in people with homozygous FH, and this is simply related to insane levels of LDL floating around in the blood.

One must wonder why LDL receptors exist in the first place if LDL were absolutely benign?

gunther gatherer said...

Hi Peter,

I'm wondering where iron intake plays a role in all of this. The official line is that high iron is supposed to cause CHD and other symptoms of metabolic disorder. But has this actually been proven?

And if it were true, wouldn't the Masai be dropping like flies? Ditto for the Inuit.

Thanks, G

Chainey said...

off topic: I remember you once writing that you preferred to stay (just) out of ketosis because you were a bit concerned about cortisol production.

I happened to stumble across a comment on this deep in the comments of Dr Eades' archives. Viz:

Commenter "Todd": The chemical that the body uses to liberate glycogen and to initiate gluconeogenesis is the stress hormone cortisol, I think. So wouldn’t IF tend to promote higher than usual cortisol levels during the fasting intervals, and is this a good thing?

Dr Eades: [M]ost of the time during fasting, the hormone glucagon,which is the counter-regulatory hormone to insulin, drives gluconeogenesis, not the stress hormone cortisol.

The above is part of a longer exchange, which you can find here

Peter said...

Hi Matthew,

Very interesting link. I'm not sure I would describe CRONies as normal people (or healthy people, I personally did not like having a BMI of 18.5, though on LC I was never hungry, I got there easily and I never dreamed of food), any more than a LC paleo eater is a normal person. Obviously Paul is likely to have achieved all of the benefits of the CRONies without the hunger and without the low cholesterol level. A fasting insulin of 5.1 +/- 2(SD) is the average for a person with a BMI of 26 on the SAD in the study. With an SD of 2 it is possible that a few of the SAD group has insulin levels below 2.0 microIU/ml, but not many.

As an aside all we need now is to see now is how well the CRONies do long term, about 100 years should do it...

Peter

Peter said...

ItsTheWoo,

Yes, this is a very valid point. But what interest me more is why one person with an LDL of 8mmol/l gets systemic cholesterol deposits (like a rabbit given oral chemical grade cholesterol dissolved in sunflower oil) yet another person with an identical LDL can be asymptomatic. The answer to that question seems quite important to me.

There are loads more post in the AGE RAGE and ALE series but it seems to have ground to a halt at the moment.

LDL receptor exist to deliver cholesterol to cells. They do this well. If they don't, there are sequences which depend on the composition of the LDL particle and other associated genes linked to the FH gene. B and G do specify that, under statins, HMG CoA reductase synthesis eventually up regulates enough to keep cells set up with cholesterol and it is hyperactive in all people with FH, hence they survive (until put on statins plus torcetrapib or ezitemebe).

Peter

Oh, and I guess you could draw a parallel with glucose. 5mmol/l is fine, 10mmol/l and IHD is coming...

Peter said...

Alex,

It is normal for FH homozygotes to be put on statins. They DO reduce cholesterol levels, but this has to be by over riding the upregulation of HMG CoA reductase which occurs in the liver. A lipophilic statin will probably cause cholesterol deficiency whole body, a water soluble statin probably hits the liver most.

Peter

Peter said...

Gunther,

Yes, iron is a good facilitator of oxidation and the linkage between excess iron storage and IHD is pretty convincing. But as you point out, carnivores would be in big trouble if that was all there was to it. I think it was Georgette on the Bernstein forum who pointed out that low iron diets were very difficult to achieve healthily and anyone with an iron storage disease needed to get treatment. It's never been something I've looked in to as blood sausage (Black pudding, which I love) in the UK is always gluten based so I don't indulge any more. Once your total protein is down at 1g/kg, your total iron intake will be way below an inuit eating 299g/d. Thinking ahead to when (if) we ever get a pig, I cannot see me wasting the blood so maybe I'll have to go hunting around Pumed more in the future...

Peter

Peter said...

Hi Chainey,

People are very interested in IF! Re the cortisol comment, I think it is the "most" people aspect that matters. Usually it's glucagon. Only if you are unlucky is it cortisol (or metabolically broken in some way???)...

Lot of people seeing the elevated fasting BG phenomenon.

Peter

gunther gatherer said...

Hi Peter,

Then maybe the iron discussion centers around iron STORAGE problems, and not actually dietary iron INGESTION. So the question to answer is what causes the liver to overstore iron?

What does the literature say on iron levels in the Masai and Inuit? OR even mercury levels in the Kitavans and Polynesians, who eat loads of fish? Is this "heavy metal-body burden" issue a real one, or is it just another symptom of eating too much White Man's Food?

Peter said...

Gunther,

I had a feeling that Anthony Colpo had bits to say about iron and, whatever else I feel about him, he is very good on facts. Checked his comments in The Great Cholesterol Con. His suggestions are that HGs exercised, which reduces ferritin count, they occasionally lost blood through trauma and they frequently lost blood chronically through hookworm infestation. The women probably lost some blood through menstruation but I've read accounts that total blood loss through this route is less in HGs is less than in moderns. Just as well, because hookworm will affect both sexes...


re heavy metals, these two are interesting

http://www.ncbi.nlm.nih.gov/pubmed/7804025

http://www.ncbi.nlm.nih.gov/pubmed/16635458

Of course you have to ask how toxic heavy metals are and, if the toxicity is mediated through free radical generation, how significant is the toxicity in a population which is both normoglycaemic and modest in its PUFA intake?

Peter

Thackray said...

Gunther,

Chapter 8 of Michael Eades’ book Protein Power Life Plan is titled “The Modern Iron Age”. Colpo (see Peter’s comment) and Eades advise against high ferritin levels. Both sources contain interesting non-overlapping information about ferritin and its effects. Russell Blaylock MD is also in the anti-iron camp bigtime.

The only way for “modern” man to lower ferritin levels is to avoid consuming high iron content foods and/or giving blood until normal levels are reached (don’t have Colpo’s or Eades’ books nearby and I forget the recommended level.)

As Peter pointed out, ancient man would have experienced considerable blood loss through various means. For this reason, we never evolved a mechanism to reduce high iron levels.

Philip Thackray

gunther gatherer said...

Hi Philip,

It still doesn't add up. This theory is implying that unless you get periodic trauma to your body which depletes you of blood (hence nutrients, minerals, etc.) and/or avoid high-iron containing foods (basically most all animal foods) which are essential to health, you will get heart disease, metabolic syndrome or both. Never mind that intentional bleeding (or looking for a fight for no other reason than in order to bleed?) is never something you see with other mammal groups or with any other animal in general.

And it still doesn't explain how the Masai and Inuit have none of these problems despite high iron (and other heavy metal) ingestion. We don't see the Inuit slashing their wrists every two months so they can be healthier.

Isn't an implication of paleolithic living supposed to be conservation of nutrients, not spilling them needlessly about the jungle?

It would make more sense to say it's the body's retention or inability to excrete these things that's the problem. And from a historical perpective, it's never seemed to be a problem until now (ie. until agriculture and neolithic living, etc.).

Thackray said...

Hi Gunther,

I just found my copy of Eades Protein Power Life Plan. His chapter on iron is 25 pages long and I found it informative and convincing. But I have no way of knowing how true his statements are. I’m not a nutritionist and his book has very few references although I trust that Dr. Eades has legitimate source material.

Not only did our ancestors bleed a lot (internal and external), but they also suffered various bacterial, viral, fungal and other parasitic diseases and parasites, all of whom take their iron needs from the bodies they inhabit thereby depleting the host body of iron. I think the Masai and the Inuit would fall into this category as well. As for other mammals, I have never seen any information about their “iron” status, although I don’t know of any mammal with our life span that consumes significant dietary iron.

When Peter is ready to make black pudding (low carb version of course) from his future pig and has “pubmeded” ferritin, I’ll be interested in his take.

By the way, Eades suggests a serum ferritin level between 10 and 50 mg/dl.

Regards,

Philip Thackray

Peter said...

Gunther,

You have a point. On a 300g/d of protein from alaskan ringed seal meat, the average intake of iron would be 10 times the current USA RDA. That's assuming they threw away the liver and blood. Then add 15g/d of combined EPA/DHA (a la Ray Peat) and these guys should be dead of IHD and cancer......

Peter

gunther gatherer said...

Peter,

If the mercury poisoning doesn't kill them first.

"Oh heavy body burden..." :-)