Wednesday, October 17, 2007

Familial Hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common genetic disease. That says something quite profound to me. If it is both genetic and common there cannot be too strong a disadvantage to it on an evolutionary basis. There are also lots and lots and lots of variants. All affect the LDL-C receptor. If you get one copy of any one of a large selection of defective receptor genes, you have quite high levels of cholesterol in your blood and... well, you know the story about clogged arteries and heart attacks. In fact, if LDL-C is such lethal stuff you would have thought that evolution would not have been so careless with the stability of the crucial piece of DNA coding for its receptor. But it wasn't careful and there are a myriad of FH variant genes. Oddly enough people in the 1800s with FH lived as long as, or even longer than, "normal" people, check out the Dutch pedigree and Utah pedigree studies.

Now this is interesting. In 1807 LDL-C at above normal levels was beneficial, particularly in Holland. In 2007 it is an automatic statin deficiency and don't try to get life insurance. What's going on?

If you ask a cardiologist about the function of the LDL-C receptor you will find that it is used by the liver to mop up that horribly artery clogging LDL-C before the patient secumbs. However, there are LDL-C receptors in other places than the liver. Such as on the endothelial cells lining the arteries. If FH sufferers have non functional receptors in their livers I am willing to bet they have poor receptors on their endothelial cells too. But wait a minute, this should be good! If you have reduced receptors you should have reduced stickiness and LESS clogging of the arteries.

But there again, the receptor is normally present and evolution does not go to the effort of building a complex structure just for the fun of wasting protein resources. No, that receptor is there for a reason, and that reason is to stick LDL-C to endothelial cells when they need it. Interestingly, isolated endothelial cells produce lots of LDL-C receptors, where as endothelial cells in contact with their brethren don't. The conclusion from this is that in areas of damage, the endothelial cells are isolated and express lots of receptors which cry out for cholesterol. In FH they don't get the cholesterol they need because the receptors don't work. Cell repair is difficult without a handy supply of lipids.

So, if you had to suggest what sort of problem might be caused by a defective cholesterol receptor, then vascular problems might be a good guess. Possibly heart attack.

NB What do you think might happen if you got two genes for a defective LDL-C receptor? This is homozygous FH. It's bad. You can see why.

So why wasn't heart attack common in FH carriers in 1807? How common was sugar in 1807? Not very. Perhaps there is a link here.

Just a minute. Where did all of that cholesterol come from in the arteries of modern sufferers? Well, you can stick LDL-C to vascular tissue with things other than the apoB-100 receptor. Try the LOX1 receptor for a start. This binds oxidised LDL-C rather nicely. Oxidised cholesterol is seriously nasty stuff. What oxidises cholesterol in your bloodstream? Try fruit and vegetables. Try sugar. Try a low fat diet. My guess is that these were thin on the ground in 1807 in Utah or Holland.

Peter

5 comments:

Lars Pergou said...

Utah:

"This suggests that some healthy life-style factors protected these men against the expression of a gene that has led to coronary disease by age 45 years in all of their heterozygous great-grandsons. One heterozygote showed a drop in serum cholesterol level from 426 to 248 mg/dL, with strict adherence to a low-fat diet without drugs."

Methinks you try too hard with little result.

HF is still the killer of the anti- lipid hypothesis mob -- as Brown and Goldstein would no doubt attest to.

Paul

Peter said...

OK, here are your problems.

That one heterozygous FH patient dropped their TC from 426 to 248 mg/dL. Neither you nor I know if this did this person any good at all. You certainly do not know.

Next, neither the Utah nor Dutch pedigree patients are likely to have eaten a low fat diet. You think they did? I think you are an idiot. Fair's fair. They will have eaten a self selected diet of the 1800s. Not low fat. They will have been hypercholesterolaemic.

What else on FH?

It's perfectly possible to discount the pleiotropic effects of statins in heart disease. These folks do a great job, presumably so do you. But not everyone can do this.

The list of effects is too long for me to ignore. Maybe you should read it. Maybe not. Shrug.

Ezitemebe plus a statin lowers cholesterol far more than the statin alone, but does no better than the statin alone.You know this is true. How come, duh???

Torcetrapib plus a statin has amazing effects on lipids, yet excess people die on the combo. Of CV events. Hmmm. Was torcetrapib so toxic it reverses the marvelous effects of having HDL >LDL?

Plasma apheresis drops LDL cholesterol. It also has marked effects on coagulation parameters. Which does the good? I disagree with you.

Liver transplants for hypercholesterolaemia: Does liver transplantation alter anything other than the expression of LDL receptors on liver cells? Does the liver make clotting factors? Have a guess.

Coagulation abnormalities are common in those families with FH and premature heart disease and in people without FH but with premature CV disease. Of course it's the lipids. Maybe. Yeah.

I presume you have excellent explanations for the results of the J-Litt and the Essen studies. Keep saying it, it's the lipids. No it's not!

Methinks you don't try at all.

I have very little free time. Tight references to support your opinions. Otherwise no thanks.

Lars said...

I only bothered to come back to this because I saw it by accident. Now I know you're a fraud.

And what on earth are those cherry-picked references supposed to prove?

So now it's coagulation factors is it? Yep, fibrinogen's a risk factor for CVD - a big one, but so what. Guess what works. Lower LDL.

The statin trials have actually made the cholesterol skeptics look like fools. Who would have thought it.

Peter said...

Hi Lars,

I note, as above, that you are wasting my time, please desist.

Peter

Unknown said...

Brilliant! Great talk that was extremely insightful and very entertaining. It's given me loads to think about.

-PPLIC